127 results on '"Krishnamurthy, Natarajan"'
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2. Collective fall arrest
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Krishnamurthy, Natarajan, primary
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- 2024
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3. Planning fall management
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Krishnamurthy, Natarajan, primary
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- 2024
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4. Conclusion
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Krishnamurthy, Natarajan, primary
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- 2024
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5. Pursuit of height
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Krishnamurthy, Natarajan, primary
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- 2024
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6. Introduction
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Krishnamurthy, Natarajan, primary
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- 2024
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7. Collective fall prevention
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Krishnamurthy, Natarajan, primary
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- 2024
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8. Other fall-related topics
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Krishnamurthy, Natarajan, primary
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- 2024
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9. Lifelines for fall devices
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Krishnamurthy, Natarajan, primary
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- 2024
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10. Individual fall arrest
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Krishnamurthy, Natarajan, primary
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- 2024
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11. A CUG codon-adapted anchor-away toolkit for functional analysis of genes in Candida albicans
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Basharat Bashir Teli, Priyanka Nagar, Yumnam Priyadarshini, Poonam Poonia, and Krishnamurthy Natarajan
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Candida albicans ,functional genomics ,anchor-away ,essential genes ,non-essential genes ,TBP1 ,Microbiology ,QR1-502 - Abstract
ABSTRACT Promoter shutoff of essential genes in the diploid Candida albicans has often been insufficient to create tight, conditional null alleles due to leaky expression and has been a stumbling block in pathogenesis research. Moreover, homozygous deletion of non-essential genes has often been problematic due to the frequent aneuploidy in the mutant strains. Rapid, conditional depletion of essential genes by the anchor-away strategy has been successfully employed in Saccharomyces cerevisiae and other model organisms. Here, rapamycin mediates the dimerization of human FK506-binding protein (FKBP12) and FKBP12-rapamycin-binding (FRB) domain-containing target protein, resulting in relocalization to altered sub-cellular locations. In this work, we used the ribosomal protein Rpl13 as the anchor and took two nuclear proteins as targets to construct a set of mutants in a proof-of-principle approach. We first constructed a rapamycin-resistant C. albicans strain by introducing a dominant mutation in the CaTOR1 gene and a homozygous deletion of RBP1, the ortholog of FKBP12, a primary target of rapamycin. The FKBP12 and the FRB coding sequences were then CUG codon-adapted for C. albicans by site-directed mutagenesis. Anchor-away strains expressing the essential TBP1 gene or the non-essential SPT8 gene as FRB fusions were constructed. We found that rapamycin caused rapid cessation of growth of the TBP-AA strain within 15 minutes and the SPT8-AA strain phenocopied the constitutive filamentous phenotype of the spt8Δ/spt8Δ mutant. Thus, the anchor-away toolbox for C. albicans developed here can be employed for genome-wide analysis to identify gene function in a rapid and reliable manner, further accelerating anti-fungal drug development in C. albicans.IMPORTANCEMolecular genetic studies thus far have identified ~27% open-reading frames as being essential for the vegetative growth of Candida albicans in rich medium out of a total 6,198 haploid set of open reading frames. However, a major limitation has been to construct rapid conditional alleles of essential C. albicans genes with near quantitative depletion of encoded proteins. Here, we have developed a toolbox for rapid and conditional depletion of genes that would aid studies of gene function of both essential and non-essential genes.
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- 2024
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12. Mycobacteria modulate SUMOylation to suppresses protective responses in dendritic cells.
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Vandana Anang, Aayushi Singh, Ankush Kumar Rana, Shakuntala Surender Kumar Saraswati, Upasana Bandyopadhyay, Chaitenya Verma, Attinder Chadha, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
Post translational modifications (PTMs) are exploited by various pathogens in order to escape host immune responses. SUMOylation is one of the PTMs which is involved in regulation of a variety of cellular responses. However, the effects of host SUMOylation on pathogenic bacteria largely remain elusive. We, therefore, investigated the role of SUMOylation in regulating defense responses in dendritic cells (DCs) during mycobacterial infection. Dendritic Cells of female BALB/c mice and THP-1 macrophages were used. Western blotting was performed to measure the expression of level of SUMO1, pSTAT1, pp38, pERK, Beclin-1, LC3, Bax and Cytochrome C. For bacterial burden confocal microscopy and CFU (Colony Forming Unit) were used. Flow cytometry was used for ROS and co-stimulatory molecules measurement. Cytokine level were measured using ELISA. We show that stimulation of Bone Marrow Derived Dendritic Cells (BMDCs) with mycobacterial antigen Rv3416 or live infection with Mycobacterium bovis BCG increases the SUMOylation of host proteins. Inhibition of SUMOylation significantly decreased intracellular bacterial loads in DCs. Additionally, inhibiting SUMOylation, induces protective immune responses by increasing oxidative burst, pro-inflammatory cytokine expression and surface expression of T cell co-stimulatory molecules, and activation of pSTAT1 and Mitogen Activated Protein Kinases (MAPK) proteins- pp38 and pERK. SUMOylation inhibition also increased apoptosis and autophagy in BMDCs. Intriguingly, mycobacteria increased SUMOylation of many of the above molecules. Furthermore, inhibiting SUMOylation in DCs primed T cells that in turn attenuated bacterial burden in infected macrophages. These findings demonstrate that SUMOylation pathway is exploited by mycobacteria to thwart protective host immune responses.
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- 2023
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13. Safety at Height
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Krishnamurthy, Natarajan, primary
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- 2024
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14. Characteristics of injuries resulting from falls from height in the construction industry
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Anantharaman, Venkataraman, primary, Zuhary, ThajudeenMohammed, additional, Ying, Hao, additional, and Krishnamurthy, Natarajan, additional
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- 2023
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15. Multiple Evolutionarily Conserved Domains of Cap2 Are Required for Promoter Recruitment and Iron Homeostasis Gene Regulation
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Manjit Kumar Srivastav, Neha Agarwal, and Krishnamurthy Natarajan
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Candida albicans ,Cap2/Hap43 ,iron homeostasis ,transcriptional regulation ,Microbiology ,QR1-502 - Abstract
ABSTRACT Iron is required for growth and metabolism by virtually all organisms. The human fungal pathogen Candida albicans has evolved multiple strategies to acquire iron. The Cap2/Hap43 transcriptional regulator, essential for robust virulence of C. albicans, controls iron homeostasis gene expression by promoter binding and repression of iron utilization genes. The expression of iron uptake genes is also dependent on Cap2, although Cap2 was not recruited to its promoters. Cap2, bearing the conserved bipartite HAP4L-bZIP domain, also contains multiple blocks of amino acids that form the highly conserved carboxyl-terminal region. In this study, we sought to identify the requirements of the different domains for Cap2 function. We constructed a series of mutants bearing either point mutations or deletions in the conserved domains and examined Cap2 activity. Deletion of the highly conserved extreme C-terminal region did not impair expression of Cap2 mutant protein but impaired cell growth and expression of iron homeostasis genes under iron-depleted conditions. Mutations in the amino-terminal HAP4L and basic leucine zipper (bZIP) domains also impaired growth and gene expression. Furthermore, chromatin immunoprecipitation (ChIP) assays showed that the HAP4L domain and the bZIP domain are both essential for Cap2 recruitment to ACO1 and CYC1 promoters. Unexpectedly, the C-terminal conserved region was also essential for Cap2 promoter recruitment. Thus, our results suggest that Cap2 employs multiple evolutionarily conserved domains, including the C-terminal domain for its transcriptional activity. IMPORTANCE Iron is an essential micronutrient for living cells. Candida albicans, the predominant human fungal pathogen, thrives under diverse environments with vastly different iron levels in the mammalian host. Therefore, to tightly control iron homeostasis, C. albicans has evolved a set of transcriptional regulators that cooperate to either upregulate or downregulate transcription of iron uptake genes or iron utilization genes. Cap2/Hap43, a critical transcriptional regulator, contains multiple conserved protein domains. In this study, we carried out mutational analyses to identify the functional roles of the conserved protein domains in Cap2. Our results show that the bZIP, HAP4L, and the C-terminal domain are each required for Cap2 transcriptional activity. Thus, Cap2 employs multiple, disparate protein domains for regulation of iron homeostasis in C. albicans.
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- 2018
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16. HSP-27 and HSP-70 negatively regulate protective defence responses from macrophages during mycobacterial infection
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Shakuntala Surender Kumar Saraswati, Ankush Kumar Rana, Aayushi Singh, Vandana Anang, Aarti Singh, and Krishnamurthy Natarajan
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Infectious Diseases ,Immunology ,Microbiology - Published
- 2023
17. Bcl2 negatively regulates Protective Immune Responses During Mycobacterial Infection
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Shakuntala Surender Kumar Saraswati, Chaitenya Verma, Upasana Bandyopadhyay, Aayushi Singh, Vandana Anang, Ankush Kumar Rana, Attinder Chadha, and Krishnamurthy Natarajan
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0301 basic medicine ,autophagy ,QH301-705.5 ,Stimulation ,Biology ,Inhibitor of apoptosis ,General Biochemistry, Genetics and Molecular Biology ,bcl2 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,Biology (General) ,neoplasms ,m. bovis bcg ,Effector ,Autophagy ,General Medicine ,immune responses ,Respiratory burst ,030104 developmental biology ,030220 oncology & carcinogenesis ,bacterial burden ,Immunology ,biological phenomena, cell phenomena, and immunity - Abstract
We previously reported that M. tb on its own as well as together with HIV inhibits macrophage apoptosis by upregulating the expression of Bcl2 and Inhibitor of Apoptosis (IAP). In addition, recent reports from our lab showed that stimulation of either macrophages or BMDCs results in the significant upregulation of Bcl2. In this report, we delineate the role of Bcl2 in mediating defense responses from dendritic cells (BMDCs) during mycobacterial infection. Inhibiting Bcl2 led to a significant decrease in intracellular bacterial burden in BMDCs. To further characterize the role of Bcl2 in modulating defense responses, we inhibited Bcl2 in BMDCs as well as human PBMCs to monitor their activation and functional status in response to mycobacterial infection and stimulation with M. tb antigen Rv3416. Inhibiting Bcl2 generated protective responses including increased expression of co-stimulatory molecules, oxidative burst, pro-inflammatory cytokine expression and autophagy. Finally, co-culturing human PBMCs and BMDCs with antigen-primed T cells increased their proliferation, activation and effector function. These results point towards a critical role for Bcl2 in regulating BMDCs defense responses to mycobacterial infection.
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- 2021
18. Calcium Dynamics Regulate Protective Responses and Growth of Staphylococcus aureus in Macrophages
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Kumar Rana Ankush, Chaitenya Verma, Krishnamurthy Natarajan, Shakuntala Surender Kumar Saraswati, Malini Shariff, Vandana Anang, Brijendra K Tiwari, and Aayushi Singh
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staphylococcus aureus ,autophagy ,QH301-705.5 ,chemistry.chemical_element ,Calcium ,Protective Agents ,General Biochemistry, Genetics and Molecular Biology ,Calcium in biology ,Mice ,Cellular and Molecular Neuroscience ,Calcium flux ,t-cell ,Extracellular ,Animals ,Homeostasis ,Biology (General) ,Cells, Cultured ,Calcium metabolism ,calcium ,Voltage-dependent calcium channel ,Macrophages ,Autophagy ,General Medicine ,Cell biology ,chemistry ,Cytokines ,phagolysosome ,Intracellular - Abstract
Staphylococcus aureus (S. aureus) is a gram-positive bacteria, which causes various fatal respiratory infections including pneumonia. The emergence of Methicillin-Resistance Staphylococcus aureus (MRSA) demands a thorough understanding of host-pathogen interactions. Here we report the role of calcium in regulating defence responses of S. aureus in macrophages. Regulating calcium fluxes in cells by different routes differentially governs the expression of T cell costimulatory molecule CD80 and Th1 promoting IL-12 receptor. Inhibiting calcium influx from extracellular medium increased expression of IFN-γ and IL-10 while blocking calcium release from the intracellular stores inhibited TGF-β levels. Blocking voltage-gated calcium channels (VGCC) inhibited the expression of multiple cytokines. While VGCC regulated the expression of apoptosis protein Bax, extracellular calcium-regulated the expression of Cytochrome-C. Similarly, VGCC regulated the expression of autophagy initiator Beclin-1. Blocking VGCC or calcium release from intracellular stores promoted phagosome-lysosome fusion, while activating VGCC inhibited phagosomelysosome fusion. Finally, calcium homeostasis regulated intracellular growth of Staphylococcus, although using different mechanisms. While blocking extracellular calcium influx seems to rely on IFN-γ and IL-12Rβ receptor mediated reduction in bacterial survival, blocking either intracellular calcium release or via VGCC route seem to rely on enhanced autophagy mediated reduction of intracellular bacterial survival. These results point to fine-tuning of defence responses by routes of calcium homeostasis.
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- 2020
19. Reconfiguration of Transcriptional Control of Lysine Biosynthesis in Candida albicans Involves a Central Role for the Gcn4 Transcriptional Activator
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Yumnam Priyadarshini and Krishnamurthy Natarajan
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Candida albicans ,lysine biosynthesis ,transcriptional regulation ,transcriptional activator ,Gcn4 ,Lys14 ,Microbiology ,QR1-502 - Abstract
ABSTRACT Evolution of transcriptional control is essential for organisms to cope with diversification into a spectrum of environments, including environments with limited nutrients. Lysine biosynthesis in fungi occurs in eight enzymatic steps. In Saccharomyces cerevisiae, amino acid starvation elicits the induction of LYS gene expression, mediated by the master regulator Gcn4 and the pathway-specific transcriptional regulator Lys14. Here, we have shown that the activation of LYS gene expression in the human fungal pathogen Candida albicans is predominantly controlled by Gcn4 under amino acid starvation conditions. Multiple lines of study showed that the four C. albicansLYS14-like genes have no role in the regulation of lysine biosynthesis. Whereas Gcn4 is dispensable for the growth of S. cerevisiae under lysine deprivation conditions, it is an essential regulator required for the growth of C. albicans under these conditions, as gcn4 deletion caused lysine auxotrophy. Gcn4 is required for the induction of increased LYS2 and LYS9 mRNA but not for the induction of increased LYS4 mRNA. Under lysine or isoleucine-valine deprivation conditions, Gcn4 recruitment to LYS2 and LYS9 promoters was induced in C. albicans. Indeed, in contrast to the S. cerevisiaeLYS gene promoters, all LYS gene promoters in C. albicans harbored a Gcn4 binding site but not all harbored the S. cerevisiae Lys14 binding site, indicating the evolutionary divergence of cis-regulatory motifs. Thus, the transcriptional rewiring of the lysine biosynthetic pathway in C. albicans involves not only neofunctionalization of the four LYS14-like genes but the attendant strengthening of control by Gcn4, indicating a coordinated response with a much broader scope for control of amino acid biosynthesis in this human pathogen. IMPORTANCE Microbes evolve rapidly so as to reconfigure their gene expression to adapt to the metabolic demands in diverse environmental niches. Here, we explored how conditions of nutrient deprivation regulate lysine biosynthesis in the human fungal pathogen Candida albicans. We show that although both Saccharomyces cerevisiae and C. albicans respond to lysine deprivation by transcriptional upregulation of lysine biosynthesis, the regulatory factors required for this control have been reconfigured in these species. We found that Gcn4 is an essential and direct transcriptional regulator of the expression of lysine biosynthetic genes under lysine starvation conditions in C. albicans. Our results therefore suggest that the regulation of the lysine biosynthetic pathway in Candida clade genomes involves gain of function by the master transcriptional regulator Gcn4, coincident with the neofunctionalization of the S. cerevisiae pathway-specific regulator Lys14.
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- 2016
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20. Suppression of Protective Responses upon Activation of L-Type Voltage Gated Calcium Channel in Macrophages during Mycobacterium bovis BCG Infection.
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Deepika Sharma, Brijendra Kumar Tiwari, Subhash Mehto, Cecil Antony, Gunjan Kak, Yogendra Singh, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection. We report that activation of VGCC during infection synergistically downmodulates the generation of oxidative burst (ROS) by macrophages. This attenuation of ROS is regulated in a manner which is dependent on Toll like Receptor (TLR) and also on the route of calcium influx, Protein Kinase C (PKC) and by Mitogen Activation Protein Kinase (MAPK) pathways. VGCC activation during infection increases cell survival and downmodulates autophagy. Concomitantly, pro-inflammatory responses such as IL-12 and IFN-γ secretion and the levels of their receptors on cell surface are inhibited. Finally, the ability of phagosomes to fuse with lysosomes in M. bovis BCG and M. tb H37Rv infected macrophages is also compromised when VGCC activation occurs during infection. The results point towards a well-orchestrated strategy adopted by mycobacteria to supress protective responses mounted by the host. This begins with the increase in the surface levels of VGCCs by mycobacteria and their antigens by well-controlled and regulated mechanisms. Subsequent activation of the upregulated VGCC following tweaking of calcium levels by molecular sensors in turn mediates suppressor responses and prepare the macrophages for long term persistent infection.
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- 2016
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21. Regulation of Interferon-γ receptor (IFN-γR) expression in macrophages during Mycobacterium tuberculosis infection
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Gunjan Kak, Yogendra Singh, Brijendra K Tiwari, and Krishnamurthy Natarajan
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0301 basic medicine ,medicine.medical_treatment ,host-pathogen interaction ,immune response ,Mice ,Homeostasis ,Macrophage ,RNA, Small Interfering ,Biology (General) ,Protein Kinase C ,Receptors, Interferon ,Mice, Inbred BALB C ,biology ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Mycobacterium bovis ,Cytokine ,tuberculosis ,Cytokines ,Female ,Tuberculosis ,MAP Kinase Signaling System ,mycobacteria ,QH301-705.5 ,ifn-γ ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mycobacterium tuberculosis ,ifn-γr ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,Downregulation and upregulation ,Antigen ,Immunity ,Endopeptidases ,medicine ,Animals ,Humans ,030102 biochemistry & molecular biology ,Macrophages ,Receptors, Interleukin-1 ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Immunology ,Leukocytes, Mononuclear ,Calcium ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 - Abstract
Interferon-gamma (IFN-γ) is a key cytokine that mediates immunity to tuberculosis (TB). Mycobacterium tuberculosis (M. tb) is known to downregulate the surface expression of IFN-γ receptor (IFN-γR) on macrophages and peripheral blood mononuclear cells (PBMCs) of patients with active TB disease. Many M. tb antigens also downmodulate IFN-γR levels in macrophages when compared with healthy controls. In the current study, we aimed at deciphering key factors involved in M. tb mediated downregulation of IFN-γR levels on macrophage surface. Our data showed that both M. tb H37Rv and M. bovis BCG infections mediate downmodulation of IFN-γR on human macrophages. This downmodulation is regulated at the level of TLR signaling pathway, second messengers such as calcium and cellular kinases i.e. PKC and ERK-MAPK, indicating that fine tuning of calcium response is critical to maintaining IFN-γR levels on macrophage surface. In addition, genes in the calcium and cysteine protease pathways which were previously identified by us to play a negative role during M. tb infection, also regulated IFN-γR expression. Thus, modulations in IFN-γR levels by utilizing host machinery may be a key immune suppressive strategy adopted by the TB pathogen to ensure its persistence and thwart host defense.
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- 2020
22. Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection.
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Cecil Antony, Subhash Mehto, Brijendra K Tiwari, Yogendra Singh, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection.
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- 2015
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23. Mycobacterium tuberculosis and Human Immunodeficiency Virus Type 1 Cooperatively Modulate Macrophage Apoptosis via Toll Like Receptor 2 and Calcium Homeostasis.
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Subhash Mehto, Cecil Antony, Nabab Khan, Rahul Arya, Arti Selvakumar, Brijendra K Tiwari, Mohit Vashishta, Yogendra Singh, Shahid Jameel, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
The emergence of drug resistant strains of Mycobacterium tuberculosis (M. tuberculosis) together with reports of co-infections with the human immunodeficiency virus (HIV) has renewed interest to better understand the intricate mechanisms prevalent during co-infections. In this study we report a synergistic effect of M. tuberculosis and HIV-1, and their antigens Rv3416 and Nef, respectively, in inhibiting apoptosis of macrophages. This inhibition involves the TLR2 pathway and second messengers that play complementing and contrasting roles in regulating apoptosis. Interestingly, the route of calcium influx into cells differentially regulates apoptosis during antigenic co-stimulation. While calcium released from intracellular stores was anti-apoptotic, calcium influx from the external milieu was pro-apoptotic. Further, molecular sensors of intracellular calcium release aid in antigen mediated inhibition of apoptosis. A cross-regulation between oxidative burst and differential routing of calcium influx governed apoptosis. Interestingly, the HIV-1 Nef supported anti-apoptotic responses in macrophages whereas Vpu had no significant effect. These results point to a synergistic liaison between M. tuberculosis and HIV-1 in regulating macrophage apoptosis.
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- 2015
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24. Pneumococal Surface Protein A (PspA) Regulates Programmed Death Ligand 1 Expression on Dendritic Cells in a Toll-Like Receptor 2 and Calcium Dependent Manner.
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Mohit Vashishta, Naeem Khan, Subhash Mehto, Devinder Sehgal, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
Pneumonia leads to high mortality in children under the age of five years worldwide, resulting in close to 20 percent of all deaths in this age group. Therefore, investigations into host-pathogen interactions during Streptococcus pneumoniae infection are key in devising strategies towards the development of better vaccines and drugs. To that end, in this study we investigated the role of S. pneumoniae and its surface antigen Pneumococcal surface protein A (PspA) in modulating the expression of co-stimulatory molecule Programmed Death Ligand 1 (PD-L1) expression on dendritic cells (DCs) and the subsequent effects of increased PD-L1 on key defence responses. Our data indicate that stimulation of DCs with PspA increases the surface expression of PD-L1 in a time and dose dependent manner. Characterization of mechanisms involved in PspA induced expression of PD-L1 indicate the involvement of Toll-Like Receptor 2 (TLR2) and calcium homeostasis. While calcium release from intracellular stores positively regulated PD-L1 expression, calcium influx from external milieu negatively regulated PD-L1 expression. Increase in PD-L1 expression, when costimulated with PspA and through TLR2 was higher than when stimulated with PspA or through TLR2. Further, knockdown of TLR2 and the intermediates in the TLR signaling machinery pointed towards the involvement of a MyD88 dependent pathway in PspA induced PD-L1 expression. Incubation of DCs with S. pneumoniae resulted in the up-regulation of PD-L1 expression, while infection with a strain lacking surface PspA failed to do so. Our data also suggests the role of PspA in ROS generation. These results suggest a novel and specific role for PspA in modulating immune responses against S. pneumoniae by regulating PD-L1 expression.
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- 2015
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25. N-acetylglucosamine kinase, Hxk1 is a multifaceted metabolic enzyme in model pathogenic yeast Candida albicans
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Kongara Hanumantha, Rao, Soumita, Paul, Krishnamurthy, Natarajan, and Swagata, Ghosh
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Fungal Proteins ,Phosphotransferases (Alcohol Group Acceptor) ,Gene Expression Regulation, Fungal ,Candida albicans ,Microbiology ,Acetylglucosamine - Abstract
The sensing of environmental conditions such as nutrient availability and the ability to adapt and respond to changing conditions are crucial for the survival of living organisms. Evidence from several organisms have revealed that some metabolic enzymes act as sensors of nutrient status and regulate the expression of sets of genes required for nutrients utilization and condition specific environmental adaptation. Thus metabolic enzymes regulate the signaling pathway by acting as transcriptional regulators and providing required metabolites. The commensal yeast, Candida albicans has recently emerged as a model system for understanding the N-acetylglucosamine (GlcNAc) signaling pathway in eukaryotes. GlcNAc kinase (Hxk1), the first enzyme of the catabolic cascade, has been shown to perform several functions such as regulation of gene expression and regulation of the metabolic status of the cell thereby resulting in a change in cell morphology (yeast-hyphal transition, white-opaque switching), metabolic gene expression, synthesis of metabolic precursors, induction of glycolytic flux rate and biofilm formation. Here, in this review we have discussed various roles of Hxk1that have not been reported in other organisms previously. The enzyme exhibits dynamic changes in subcellular localization consistent with its expanded functions inside the cell. Thus Hxk1 in C. albicans orchestrates several dynamic cellular processes and this signaling system can act as a paradigm to understand the cell fate and metabolic specialization in other eukaryotes too. Still, the molecular cues involved in Hxk1 mediating functions are yet to be unveiled; the relationship between Hxk1 sensing and its signaling effects is also not understood yet.
- Published
- 2022
26. Bcl2 negatively regulates Protective Immune Responses During
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Aayushi, Singh, Vandana, Anang, Chaitenya, Verma, Shakuntala Surender Kumar, Saraswati, Ankush Kumar, Rana, Upasana, Bandyopadhyay, Attinder, Chadha, and Krishnamurthy, Natarajan
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Mice, Inbred BALB C ,Mycobacterium Infections ,Macrophages ,Immunity ,Apoptosis ,Dendritic Cells ,Mycobacterium bovis ,Mice ,Proto-Oncogene Proteins c-bcl-2 ,Autophagy ,Animals ,Cytokines ,Humans ,Female - Abstract
We previously reported that
- Published
- 2021
27. Myg1 exonuclease couples the nuclear and mitochondrial translational programs through RNA processing
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Ayush Aggarwal, Vivek T. Natarajan, Archana Vats, Shaunak A Burse, Ritika Grover, Rakesh Sharma, Ashwini Kumar Ray, Soumya Sinha Roy, Lipi Thukral, Rajpal Srivastav, Rajesh S. Gokhale, Kiran Narta, Krishnamurthy Natarajan, Garima Malik, Sudha Bhattacharya, Shambhavi Shankrit, Kritika Kirty, Rajesh Pandey, Rajender K. Motiani, and Mitali Mukerji
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Exonuclease ,Exonucleases ,Quality Control ,Nucleolus ,RNase P ,Vitiligo ,Saccharomyces cerevisiae ,Biology ,Ribosome ,Ribosome assembly ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Endoribonucleases ,Genetics ,medicine ,Animals ,Humans ,030304 developmental biology ,Cell Nucleus ,0303 health sciences ,Nucleic Acid Enzymes ,Cytoplasmic translation ,RNA ,Nuclear Proteins ,Proteins ,Sequence Analysis, DNA ,Cell biology ,Mitochondria ,Cell nucleus ,medicine.anatomical_structure ,RNA, Ribosomal ,Protein Biosynthesis ,biology.protein ,Ribosomes ,030217 neurology & neurosurgery ,Cell Nucleolus - Abstract
Semi-autonomous functioning of mitochondria in eukaryotic cell necessitates coordination with nucleus. Several RNA species fine-tune mitochondrial processes by synchronizing with the nuclear program, however the involved components remain enigmatic. In this study, we identify a widely conserved dually localized protein Myg1, and establish its role as a 3′-5′ RNA exonuclease. We employ mouse melanoma cells, and knockout of the Myg1 ortholog in Saccharomyces cerevisiae with complementation using human Myg1 to decipher the conserved role of Myg1 in selective RNA processing. Localization of Myg1 to nucleolus and mitochondrial matrix was studied through imaging and confirmed by sub-cellular fractionation studies. We developed Silexoseqencing, a methodology to map the RNAse trail at single-nucleotide resolution, and identified in situ cleavage by Myg1 on specific transcripts in the two organelles. In nucleolus, Myg1 processes pre-ribosomal RNA involved in ribosome assembly and alters cytoplasmic translation. In mitochondrial matrix, Myg1 processes 3′-termini of the mito-ribosomal and messenger RNAs and controls translation of mitochondrial proteins. We provide a molecular link to the possible involvement of Myg1 in chronic depigmenting disorder vitiligo. Our study identifies a key component involved in regulating spatially segregated organellar RNA processing and establishes the evolutionarily conserved ribonuclease as a coordinator of nucleo-mitochondrial crosstalk.
- Published
- 2019
28. Reciprocal regulation of reactive oxygen species and phospho-CREB regulates voltage gated calcium channel expression during Mycobacterium tuberculosis infection.
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Arti Selvakumar, Cecil Antony, Jhalak Singhal, Brijendra K Tiwari, Yogendra Singh, and Krishnamurthy Natarajan
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Medicine ,Science - Abstract
Our previous work has demonstrated the roles played by L-type Voltage Gated Calcium Channels (VGCC) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. Here we decipher mechanisms and pathways engaged by the pathogen to regulate VGCC expression in macrophages. We show that M. tb and its antigen Rv3416 use phospho-CREB (pCREB), Reactive Oxygen Species (ROS), Protein Kinase C (PKC) and Mitogen Activated Protein Kinase (MAPK) to modulate VGCC expression in macrophages. siRNA mediated knockdown of MyD88, IRAK1, IRAK2 or TRAF6 significantly inhibited antigen mediated VGCC expression. Inhibiting Protein Kinase C (PKC) or MEK-ERK1/2 further increased VGCC expression. Interestingly, inhibiting intracellular calcium release upregulated antigen mediated VGCC expression, while inhibiting extracellular calcium influx had no significant effect. siRNA mediated knockdown of transcription factors c-Jun, SOX5 and CREB significantly inhibited Rv3416 mediated VGCC expression. A dynamic reciprocal cross-regulation between ROS and pCREB was observed that in turn governed VGCC expression with ROS playing a limiting role in the process. Further dissection of the mechanisms such as the interplay between ROS and pCREB would improve our understanding of the regulation of VGCC expression during M. tb infection.
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- 2014
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29. Correction: N-Acetylglucosamine Kinase, Is Involved in Morphogenetic Transition and Metabolic Gene Expression in.
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Kongara Hanumantha Rao, Swagata Ghosh, Krishnamurthy Natarajan, and Asis Datta
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Medicine ,Science - Published
- 2013
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30. N-acetylglucosamine kinase, HXK1 is involved in morphogenetic transition and metabolic gene expression in Candida albicans.
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Kongara Hanumantha Rao, Swagata Ghosh, Krishnamurthy Natarajan, and Asis Datta
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Medicine ,Science - Abstract
Candida albicans, a common fungal pathogen which diverged from the baker's yeast Saccharomyces cerevisiae has the unique ability to utilise N-acetylglucosamine, an amino sugar and exhibits phenotypic differences. It has acquired intricate regulatory mechanisms at different levels in accordance with its life style. N-acetylglucosamine kinase, a component of the N-acetylglucosamine catabolic cascade is an understudied gene since Saccharomyces cerevisiae lacks it. We report HXK1 to act as both positive and negative regulator of transcription of genes involved in maintaining cellular homeostasis. It is involved in repression of hyphal specific genes in addition to metabolic genes. Its regulation of filamentation and GlcNAc metabolism is independent of the known classical regulators like EFG1, CPH1, RAS1, TPK2 or TUP1. Moreover, Hxk1-GFP is localised to cytoplasm, nucleus and mitochondria in a condition specific manner. By employing two-step affinity purification, we report the interaction of HXK1 with SIR2 under filamentation inducing conditions. Our work highlights a novel regulatory mechanism involved in filamentation repression and attempts to decipher the GlcNAc catabolic regulatory cascade in eukaryotes.
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- 2013
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31. Biochemical characterization of Plasmodium complement factors binding protein for its role in immune modulation
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Asif Mohmmed, Sumit Rathore, Shweta Sharma, Kalamuddin, Dinesh Gupta, Ashutosh Panda, Mohit Vashishta, Pawan Malhotra, Khushboo Rawat, Krishnamurthy Natarajan, Bishwanath Kumar Chourasia, Gourab Paul, Arunaditya Deshmukh, Jhalak Singhal, Shreyansh Tatiya, Rajan Pandey, and Gautam Kumar
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0301 basic medicine ,030102 biochemistry & molecular biology ,Effector ,Binding protein ,Cell Biology ,Biology ,biology.organism_classification ,Biochemistry ,Complement (complexity) ,Cell biology ,Complement system ,03 medical and health sciences ,030104 developmental biology ,Immune system ,parasitic diseases ,biology.protein ,Plasmodium berghei ,Receptor ,Molecular Biology ,Complement control protein - Abstract
Complement system is the first line of human defence against intruding pathogens and is recognized as a potentially useful therapeutic target. Human malaria parasite Plasmodium employs a series of intricate mechanisms that enables it to evade different arms of immune system, including the complement system. Here, we show the expression of a multi-domain Plasmodium Complement Control Protein 1, PfCCp1 at asexual blood stages and its binding affinity with C3b as well as C4b proteins of human complement cascade. Using a biochemical assay, we demonstrate that PfCCp1 binds with complement factors and inhibits complement activation. Active immunization of mice with PfCCp1 followed by challenge with Plasmodium berghei resulted in the loss of biphasic growth of parasites and early death in comparison to the control group. The study also showed a role of PfCCp1 in modulating Toll-like receptor (TLR)-mediated signalling and effector responses on antigen-presenting cells. PfCCp1 binds with dendritic cells that down-regulates the expression of signalling molecules and pro-inflammatory cytokines, thereby dampening the TLR2-mediated signalling; hence acting as a potent immuno-modulator. In summary, PfCCp1 appears to be an important component of malaria parasite directed immuno-modulating strategies that promote the adaptive fitness of pathogens in the host.
- Published
- 2018
32. Mutational analysis of<scp>TAF</scp>6 revealed the essential requirement of the histone‐fold domain and the<scp>HEAT</scp>repeat domain for transcriptional activation
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Rashmi Dahiya and Krishnamurthy Natarajan
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Models, Molecular ,Transcriptional Activation ,0301 basic medicine ,Saccharomyces cerevisiae Proteins ,Protein subunit ,DNA Mutational Analysis ,Protein domain ,Mutant ,Saccharomyces cerevisiae ,Biochemistry ,03 medical and health sciences ,Protein Domains ,Gene Expression Regulation, Fungal ,Molecular Biology ,TATA-Binding Protein Associated Factors ,Binding Sites ,Chemistry ,food and beverages ,Cell Biology ,Cell biology ,SAGA complex ,030104 developmental biology ,Mutation ,Transcription Factor TFIID ,Histone fold ,Transcription factor II D - Abstract
TAF6, bearing the histone H4-like histone-fold domain (HFD), is a subunit of the core TAF module in TFIID and SAGA transcriptional regulatory complexes. We isolated and characterized several yeast TAF6 mutants bearing amino acid substitutions in the HFD, the middle region or the HEAT repeat domain. The TAF6 mutants were highly defective for transcriptional activation by the Gcn4 and Gal4 activators. CHIP assays showed that the TAF6-HFD and the TAF6-HEAT domain mutations independently abrogated the promoter occupancy of TFIID and SAGA complex in vivo. We employed genetic and biochemical assays to identify the relative contributions of the TAF6 HFD and HEAT domains. First, the temperature-sensitive phenotype of the HEAT domain mutant was suppressed by overexpression of the core TAF subunits TAF9 and TAF12, as well as TBP. The HFD mutant defect, however, was suppressed by TAF5 but not by TAF9, TAF12 or TBP. Second, the HEAT mutant but not the HFD mutant was defective for growth in the presence of transcription elongation inhibitors. Third, coimmunoprecipitation assays using yeast cell extracts indicated that the specific TAF6 HEAT domain residues are critical for the interaction of core TAF subunits with the SAGA complex but not with TFIID. The specific HFD residues in TAF6, although required for heterodimerization between TAF6 and TAF9 recombinant proteins, were dispensable for association of the core TAF subunits with TFIID and SAGA in yeast cell extracts. Taken together, the results of our studies have uncovered the non-overlapping requirement of the evolutionarily conserved HEAT domain and the HFD in TAF6 for transcriptional activation.
- Published
- 2018
33. Characterization of Leishmania donovani aquaporins shows presence of subcellular aquaporins similar to tonoplast intrinsic proteins of plants.
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Neha Biyani, Swati Mandal, Chandan Seth, Malika Saint, Krishnamurthy Natarajan, Indira Ghosh, and Rentala Madhubala
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Medicine ,Science - Abstract
Leishmania donovani, a protozoan parasite, resides in the macrophages of the mammalian host. The aquaporin family of proteins form important components of the parasite-host interface. The parasite-host interface could be a potential target for chemotherapy. Analysis of L. major and L. infantum genomes showed the presence of five aquaporins (AQPs) annotated as AQP9 (230aa), AQP putative (294aa), AQP-like protein (279aa), AQP1 (314aa) and AQP-like protein (596aa). We report here the structural modeling, localization and functional characterization of the AQPs from L. donovani. LdAQP1, LdAQP9, LdAQP2860 and LdAQP2870 have the canonical NPA-NPA motifs, whereas LdAQP putative has a non-canonical NPM-NPA motif. In the carboxyl terminal to the second NPA box of all AQPs except AQP1, a valine/alanine residue was found instead of the arginine. In that respect these four AQPs are similar to tonoplast intrinsic proteins in plants, which are localized to intracellular organelles. Confocal microscopy of L. donovani expressing GFP-tagged AQPs showed an intracellular localization of LdAQP9 and LdAQP2870. Real-time PCR assays showed expression of all aquaporins except LdAQP2860, whose level was undetectable. Three-dimensional homology modeling of the AQPs showed that LdAQP1 structure bears greater topological similarity to the aquaglyceroporin than to aquaporin of E. coli. The pore of LdAQP1 was very different from the rest in shape and size. The cavity of LdAQP2860 was highly irregular and undefined in geometry. For functional characterization, four AQP proteins were heterologously expressed in yeast. In the fps1Δ yeast cells, which lacked the key aquaglyceroporin, LdAQP1 alone displayed an osmosensitive phenotype indicating glycerol transport activity. However, expression of LdAQP1 and LdAQP putative in a yeast gpd1Δ strain, deleted for glycerol production, conferred osmosensitive phenotype indicating water transport activity or aquaporin function. Our analysis for the first time shows the presence of subcellular aquaporins and provides structural and functional characterization of aquaporins in Leishmania donovani.
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- 2011
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34. Suppression of Toll-like receptor 2–mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c
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Attinder Chadha, Priya Gupta, Brijendra K Tiwari, Krishnamurthy Natarajan, Upasana Bandyopadhyay, K K Bhattacharyya, Yogendra Singh, Vani Brahamachari, Pawan Malhotra, Sonam Popli, and Rajagopal Raman
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0301 basic medicine ,Toll-like receptor ,Innate immune system ,Immunology ,Signal transducing adaptor protein ,Cell Biology ,Biology ,Cell biology ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,Immune system ,Immunology and Allergy ,Secretion ,Transcription factor ,Death domain - Abstract
Microorganisms are known to devise various strategies to thwart protective responses by the host. One such strategy is to incorporate sequences and domains in their genes/proteins that have similarity to various domains of the host proteins. In this study, we report that Mycobacterium tuberculosis protein Rv3529c exhibits significant similarity to the death domain of the TLR pathway adaptor protein MyD88. Incubation of macrophages with Rv3529c specifically inhibited TLR2-mediated proinflammatory responses. This included attenuated oxidative burst, reduced phosphorylation of MAPK-ERK, reduced activation of transcription factor NF-κB and reduced secretion of proinflammatory cytokines IFN-γ, IL-6, and IL-17A with a concomitant increased secretion of suppressor cytokines IL-10 and TGF-β. Importantly, Rv3529c significantly inhibited TLR2-induced association of MyD88 with IRAK1 by competitively binding with IRAK1. Further, Rv3529c mediated inhibition of apoptosis and phagosome–lysosome fusion. Lastly, incubation of macrophages with Rv3529c increased bacterial burden inside macrophages. The data presented show another strategy evolved by M. tuberculosis toward immune evasion that centers on incorporating sequences in proteins that are similar to crucial proteins in the innate immune system of the host.
- Published
- 2017
35. Phenylalanine-rich peptides potently bind ESAT6, a virulence determinant of Mycobacterium tuberculosis, and concurrently affect the pathogen's growth.
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Krishan Kumar, Megha Tharad, Swetha Ganapathy, Geeta Ram, Azeet Narayan, Jameel Ahmad Khan, Rana Pratap, Anamika Ghosh, Sachin Kumar Samuchiwal, Sushil Kumar, Kuhulika Bhalla, Deepti Gupta, Krishnamurthy Natarajan, Yogendra Singh, and Anand Ranganathan
- Subjects
Medicine ,Science - Abstract
BACKGROUND:The secretory proteins of Mycobacterium tuberculosis (M. tuberculosis) have been known to be involved in the virulence, pathogenesis as well as proliferation of the pathogen. Among this set, many proteins have been hypothesized to play a critical role at the genesis of the onset of infection, the primary site of which is invariably the human lung. METHODOLOGY/PRINCIPAL FINDINGS:During our efforts to isolate potential binding partners of key secretory proteins of M. tuberculosis from a human lung protein library, we isolated peptides that strongly bound the virulence determinant protein Esat6. All peptides were less than fifty amino acids in length and the binding was confirmed by in vivo as well as in vitro studies. Curiously, we found all three binders to be unusually rich in phenylalanine, with one of the three peptides a short fragment of the human cytochrome c oxidase-3 (Cox-3). The most accessible of the three binders, named Hcl1, was shown also to bind to the Mycobacterium smegmatis (M. smegmatis) Esat6 homologue. Expression of hcl1 in M. tuberculosis H37Rv led to considerable reduction in growth. Microarray analysis showed that Hcl1 affects a host of key cellular pathways in M. tuberculosis. In a macrophage infection model, the sets expressing hcl1 were shown to clear off M. tuberculosis in much greater numbers than those infected macrophages wherein the M. tuberculosis was not expressing the peptide. Transmission electron microscopy studies of hcl1 expressing M. tuberculosis showed prominent expulsion of cellular material into the matrix, hinting at cell wall damage. CONCLUSIONS/SIGNIFICANCE:While the debilitating effects of Hcl1 on M. tuberculosis are unrelated and not because of the peptide's binding to Esat6-as the latter is not an essential protein of M. tuberculosis-nonetheless, further studies with this peptide, as well as a closer inspection of the microarray data may shed important light on the suitability of such small phenylalanine-rich peptides as potential drug-like molecules against this pathogen.
- Published
- 2009
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36. Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
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Shashank Gupta, Nasir Salam, Varsha Srivastava, Rupak Singla, Digamber Behera, Khalid U Khayyam, Reshma Korde, Pawan Malhotra, Rajiv Saxena, and Krishnamurthy Natarajan
- Subjects
Medicine ,Science - Abstract
Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs) either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity.
- Published
- 2009
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37. Protective immunity to Mycobacterium tuberculosis infection by chemokine and cytokine conditioned CFP-10 differentiated dendritic cells.
- Author
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Nasir Salam, Shashank Gupta, Sachin Sharma, Shweta Pahujani, Aprajita Sinha, Rajiv K Saxena, and Krishnamurthy Natarajan
- Subjects
Medicine ,Science - Abstract
BackgroundDendritic cells (DCs) play major roles in mediating immune responses to mycobacteria. A crucial aspect of this is the priming of T cells via chemokines and cytokines. In this study we investigated the roles of chemokines RANTES and IP-10 in regulating protective responses from Mycobacterium tuberculosis (M. tb) 10 kDa Culture Filtrate Protein-10 (CFP-10) differentiated DCs (CFP10-DCs).Methods and findingsInfection of CFP10-DCs with mycobacteria down-modulated RANTES and IP-10 levels. Pathway specific microarray analyses showed that in addition to RANTES and IP-10, mycobacteria infected CFP10-DCs showed reduced expression of many Th1 promoting chemokines and chemokine receptors. Importantly, T cells co-cultured with RANTES and IP-10 conditioned CFP10-DCs mediated killing of mycobacteria from infected macrophages. Similarly, T cells recruited by RANTES and IP-10 conditioned CFP10-DCs mediated significant killing of mycobacteria from infected macrophages. IFN-gamma treatment of CFP10-DCs restored RANTES and IP-10 levels and T cells activated by these DCs mediated significant killing of virulent M. tb inside macrophages. Adoptive transfer of either RANTES and IP-10 or IL-12 and IFN-gamma conditioned CFP10-DCs cleared an established M. tb infection in mice. The extent of clearance was similar to that obtained with drug treatment.ConclusionsThese results indicate that chemokine and cytokine secretion by DCs differentiated by M. tb antigens such as CFP-10 play major roles in regulating protective immune responses at sites of infection.
- Published
- 2008
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38. Interplay between transcriptional regulators and the SAGA chromatin modifying complex fine-tune iron homeostasis
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Krishnamurthy Natarajan, Neha Agarwal, Poonam Poonia, and Manjit Kumar Srivastav
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0301 basic medicine ,HAP complex ,Transcription, Genetic ,SAGA complex ,RNA polymerase II ,Biochemistry ,HAP43 ,Histones ,chromatin modification ,Gene Expression Regulation, Fungal ,Candida albicans ,Homeostasis ,−Fe, supplemented with BPS ,BPS, bathophenanthrolinedisulfonic acid ,Promoter Regions, Genetic ,transcription factor ,SAGA, Spt-Ada-Gcn5-Acetyl transferase ,Regulation of gene expression ,biology ,Chemistry ,Acetylation ,Chromatin ,Cell biology ,CAP2 ,RNA Polymerase II ,Research Article ,Iron ,Repressor ,Fungal Proteins ,03 medical and health sciences ,CoIP, coimmunoprecipitation ,Molecular Biology ,Transcription factor ,Binding Sites ,Base Sequence ,Models, Genetic ,030102 biochemistry & molecular biology ,Lysine ,Promoter ,FAS, ferrous ammonium sulfate ,+Fe, supplemented with FAS ,Cell Biology ,Protein Subunits ,030104 developmental biology ,Multiprotein Complexes ,biology.protein ,iron homeostasis ,SC-LIM, synthetic complete–low iron media ,gene regulation ,Chromatin immunoprecipitation ,SEF1 ,Transcription Factors - Abstract
The human fungal pathogen Candida albicans responds to iron deprivation by a global transcriptome reconfiguration known to be controlled by the transcriptional regulators Hap43 (also known as Cap2), Sef1, and the trimeric Hap2-Hap3-Hap5 complex. However, the relative roles of these regulators are not known. To dissect this system, we focused on the FRP1 and ACO1 genes, which are induced and repressed, respectively, under iron deprivation conditions. Chromatin immunoprecipitation assays showed that the trimeric HAP complex and Sef1 are recruited to both FRP1 and ACO1 promoters. While the HAP complex occupancy at the FRP1 promoter was Sef1-dependent, occupancy of Sef1 was not dependent on the HAP complex. Furthermore, iron deprivation elicited histone H3-Lys9 hyperacetylation and Pol II recruitment mediated by the trimeric HAP complex and Sef1 at the FRP1 promoter. In contrast, at the ACO1 promoter, the HAP trimeric complex and Hap43 promoted histone deacetylation and also limited Pol II recruitment under iron deprivation conditions. Mutational analysis showed that the SAGA subunits Gcn5, Spt7, and Spt20 are required for C. albicans growth in iron-deficient medium and for H3-K9 acetylation and transcription from the FRP1 promoter. Thus, the trimeric HAP complex promotes FRP1 transcription by stimulating H3K9Ac and Pol II recruitment and, along with Hap43, functions as a repressor of ACO1 by maintaining a deacetylated promoter under iron-deficient conditions. Thus, a regulatory network involving iron-responsive transcriptional regulators and the SAGA histone modifying complex functions as a molecular switch to fine-tune tight control of iron homeostasis gene expression in C. albicans.
- Published
- 2021
39. Aedes aegypti lachesin protein binds to the domain III of envelop protein of Dengue virus-2 and inhibits viral replication
- Author
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Sujatha Sunil, Sonam Popli, Ankit Kumar, Gunjan Kumar Saurav, Karuna Yadav, Vipin Singh Rana, Krishnamurthy Natarajan, Raman Rajagopal, Om P. Singh, and Narendra Kumar
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Phage display ,viruses ,Immunology ,Immunoglobulins ,Aedes aegypti ,Mosquito Vectors ,Dengue virus ,medicine.disease_cause ,Virus Replication ,Microbiology ,Virus ,Salivary Glands ,Dengue ,03 medical and health sciences ,Viral Envelope Proteins ,Viral entry ,Aedes ,Virology ,medicine ,Animals ,Peptide sequence ,030304 developmental biology ,0303 health sciences ,biology ,030306 microbiology ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Dengue Virus ,biology.organism_classification ,Quaternary Ammonium Compounds ,Viral replication ,biology.protein ,Female ,Antibody - Abstract
Dengue virus (DENV) comprises of four serotypes (DENV-1 to -4) and is medically one of the most important arboviruses (arthropod-borne virus). DENV infection is a major human health burden and is transmitted between humans by the insect vector, Aedes aegypti. Ae. aegypti ingests DENV while feeding on infected humans, which traverses through its gut, haemolymph and salivary glands of the mosquito before being injected into a healthy human. During this process of transmission, DENV must interact with many proteins of the insect vector, which are important for its successful transmission. Our study focused on the identification and characterisation of interacting protein partners in Ae. aegypti to DENV. Since domain III (DIII) of envelope protein (E) is exposed on the virion surface and is involved in virus entry into various cells, we performed phage display library screening against domain III of the envelope protein (EDIII) of DENV-2. A peptide sequence showing similarity to lachesin protein was found interacting with EDIII. The lachesin protein was cloned, heterologously expressed, purified and used for in vitro interaction studies. Lachesin protein interacted with EDIII and also with DENV. Further, lachesin protein was localised in neuronal cells of different organs of Ae. aegypti by confocal microscopy. Blocking of lachesin protein in Ae. aegypti with anti-lachesin antibody resulted in a significant reduction in DENV replication.
- Published
- 2019
40. 2-deoxy-D-Glucose-(2-DG) Prevents Pathogen Driven Acute Inflammation and Associated toxicity
- Author
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Krishnamurthy Natarajan, Bilikere S. Dwarakanath, Sanjay Pandey, Saurabh Singh, Vandana Anang, and Anant Narayan Bhatt
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Health (social science) ,Chemistry ,Inflammation ,Pharmacology ,Health Professions (miscellaneous) ,chemistry.chemical_compound ,Abstracts ,Biology of Aging ,Toxicity ,medicine ,medicine.symptom ,Life-span and Life-course Studies ,2-Deoxy-D-glucose ,AcademicSubjects/SOC02600 ,Pathogen ,Session 10160 (Late Breaking Poster) - Abstract
Pathogen-associated molecular patterns (PAMPs) associated with viral and bacterial infections trigger multiple inflammatory pathways which may result in oxidative stress driven toxicity, tissue fibrosis organ dysfunction and ageing. Inflammatory events need high energy demands and predominantly depends on the glycolysis. Thus, energy metabolism of the inflammatory events can be targeted to reducing the magnitude of the PAMPs driven inflammation and preventing tissue toxicity. Here we propose that 2-DG, a glycolytic inhibitor, and a potential Energy Restriction Mimetic agent (ERMA) can modulate inflammatory events and can prevent the development of acute as well as chronic pathology. For this study we induced LPS (bacterial PAMP) induced endotoxemia in mice which models infection associated inflammatory acute inflammatory events, tissue damage and organ dysfunction. 2-DG fed mice (0.4% w/v in drinking water) showed reduced LPS driven oxidative stress and capillary damage in lungs. Administration of 2-DG also reduced LPS induced spike in inflammatory cytokines (TNF, IL6 and IL1β) in the BALF and serum. Lungs of 2-DG fed mice showed lesser infiltration of inflammatory cells and reduced inflammatory signaling activation. 2-DG also downregulated the ex-vivo and in-vivo migration of the PMNCs. Furthermore, 2-DG also reduced the activation of the macrophage cells (RAW264.7) which was seen with reduction and the glycolysis and increased mitochondrial functions. Our data suggest that 2-DG administration as ERMA in drinking water can prevent pathogenic exposure driven inflammatory events which may prevent acute as well as chronic inflammatory disorders.
- Published
- 2020
41. Dietary Administration of 2-Deoxy-D-Glucose Reduces High Fat Diet Induced Obesity and meta-inflammation in Mice
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Sushma Ray, Krishnamurthy Natarajan, Bilikere S. Dwarakanath, Sanjay Pandey, Saurabh Singh, Diksha Joshi, and Anant Narayan Bhatt
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medicine.medical_specialty ,Health (social science) ,business.industry ,Inflammation ,Session 10340 (Late Breaking Poster) ,Health Professions (miscellaneous) ,Abstracts ,High fat diet induced obesity ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Nutrition | Obesity & Eating Disorders ,Internal medicine ,Medicine ,medicine.symptom ,AcademicSubjects/SOC02600 ,Life-span and Life-course Studies ,business ,2-Deoxy-D-glucose - Abstract
Obesity is a major risk factor for type 2 diabetes, NAFLD, chronic diseases and cancer. Insulin resistance, oxidative stress, high ectopic lipid levels and meta-inflammation are the mechanisms proposed to play a leading role in the morbidity associated with obesity. Energy restriction mimetics (ERMAs) has also been shown earlier to reduce the scale and the severity of these disorders by mimicking the physiological effects of the Energy Restriction. In present study we propose that the use of 2-DG as ERMA can be effective in regulating the High Fat Diet (HFD) induced obesity. Effect of 2-DG (0.4% w/v in drinking water) on the HFD and Insulin Resistance (IR). HFD induced change in body weight, adipose tissue mass, and ectopic lipid levels was assessed as the measure of obesity.IR and glucose levels were also estimated to evaluate the effect of 2-DG on the insulin sensitivity in HFD mice. 2-DG significantly altered HFD induced increase in the mice body weight, epididymal White Adipose Tissue (WAT) and liver weight. 2-DG fed mice also showed reduced lipid levels in serum and liver. Furthermore, 2-DG also reduced the oxidative damage in the liver with concomitant increase in enzymatic (SOD and Catalase) and non-enzymatic (reduced Glutathione) antioxidant levels. 2-DG fed mice also showed reduced levels of Leptin, IL-6 and TGF-β which are early drivers of the etiology of the metabolic diseases. Our results suggest that 2-DG as ERMA can prevent obesity and etiology of associated disorders. However, more relevant models are needed to further strengthen these observation
- Published
- 2020
42. Deciphering the role of calcium homeostasis in T cells functions during mycobacterial infection
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Krishnamurthy Natarajan, Vandana Anang, Aarti Singh, Ankush Kumar Rana, Shakuntala Surender Kumar Saraswati, Aayushi Singh, Priyanka Kumari, and Chaitenya Verma
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0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,chemistry.chemical_element ,Apoptosis ,Biology ,Calcium ,Lymphocyte Activation ,Mycobacterium ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Autophagy ,medicine ,Animals ,Homeostasis ,Tuberculosis ,Calcium metabolism ,Mice, Inbred BALB C ,Mycobacterium Infections ,Voltage-dependent calcium channel ,Effector ,Macrophages ,Mycobacterium tuberculosis ,Cell biology ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,chemistry ,Cytokines ,Interleukin-2 ,Female ,Calcium Channels ,030215 immunology - Abstract
Calcium plays an important role in regulating cell physiology and immune responses to various pathogens. Our recent work has highlighted the crucial role for calcium homeostasis in dendritic cells and macrophages during various infections. Here we investigated the effect of calcium homeostasis in regulating T cell activation and function during mycobacterial infection. Results show that calcium homeostasis had varied effects in regulating T cell activation and function during mycobacterial infection. This included regulation of the expression of co-stimulatory molecules, cytokine profiles and effector function. A net negative role for Voltage Gated Calcium Channel (VGCC) was observed. Inhibiting VGCC in mycobacteria primed T cells induced increased production of pro-inflammatory cytokines and an increased effector phenotype. Infected macrophages when incubated with VGCC inhibited T cells, induced increased expression of co-stimulatory molecule expression on macrophages, increased the production of pro-inflammatory cytokines and increased autophagy and apoptosis. This collectively led to reduced survival of mycobacteria inside macrophages. The data point towards a fine regulation of protective responses by routes of calcium influx and release that mediate pathogen survival or clearance.
- Published
- 2020
43. Multiple Evolutionarily Conserved Domains of Cap2 Are Required for Promoter Recruitment and Iron Homeostasis Gene Regulation
- Author
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Neha Agarwal, Krishnamurthy Natarajan, and Manjit Kumar Srivastav
- Subjects
0301 basic medicine ,Molecular Biology and Physiology ,Chromatin Immunoprecipitation ,Iron ,Cap2/Hap43 ,Protein domain ,lcsh:QR1-502 ,Biology ,Microbiology ,lcsh:Microbiology ,Fungal Proteins ,03 medical and health sciences ,Mutant protein ,Gene Expression Regulation, Fungal ,Candida albicans ,Transcriptional regulation ,Homeostasis ,transcriptional regulation ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Conserved Sequence ,Regulation of gene expression ,030102 biochemistry & molecular biology ,Virulence ,bZIP domain ,Promoter ,QR1-502 ,Cell biology ,030104 developmental biology ,iron homeostasis ,Chromatin immunoprecipitation ,Research Article ,Transcription Factors - Abstract
Iron is an essential micronutrient for living cells. Candida albicans, the predominant human fungal pathogen, thrives under diverse environments with vastly different iron levels in the mammalian host. Therefore, to tightly control iron homeostasis, C. albicans has evolved a set of transcriptional regulators that cooperate to either upregulate or downregulate transcription of iron uptake genes or iron utilization genes. Cap2/Hap43, a critical transcriptional regulator, contains multiple conserved protein domains. In this study, we carried out mutational analyses to identify the functional roles of the conserved protein domains in Cap2. Our results show that the bZIP, HAP4L, and the C-terminal domain are each required for Cap2 transcriptional activity. Thus, Cap2 employs multiple, disparate protein domains for regulation of iron homeostasis in C. albicans., Iron is required for growth and metabolism by virtually all organisms. The human fungal pathogen Candida albicans has evolved multiple strategies to acquire iron. The Cap2/Hap43 transcriptional regulator, essential for robust virulence of C. albicans, controls iron homeostasis gene expression by promoter binding and repression of iron utilization genes. The expression of iron uptake genes is also dependent on Cap2, although Cap2 was not recruited to its promoters. Cap2, bearing the conserved bipartite HAP4L-bZIP domain, also contains multiple blocks of amino acids that form the highly conserved carboxyl-terminal region. In this study, we sought to identify the requirements of the different domains for Cap2 function. We constructed a series of mutants bearing either point mutations or deletions in the conserved domains and examined Cap2 activity. Deletion of the highly conserved extreme C-terminal region did not impair expression of Cap2 mutant protein but impaired cell growth and expression of iron homeostasis genes under iron-depleted conditions. Mutations in the amino-terminal HAP4L and basic leucine zipper (bZIP) domains also impaired growth and gene expression. Furthermore, chromatin immunoprecipitation (ChIP) assays showed that the HAP4L domain and the bZIP domain are both essential for Cap2 recruitment to ACO1 and CYC1 promoters. Unexpectedly, the C-terminal conserved region was also essential for Cap2 promoter recruitment. Thus, our results suggest that Cap2 employs multiple evolutionarily conserved domains, including the C-terminal domain for its transcriptional activity. IMPORTANCE Iron is an essential micronutrient for living cells. Candida albicans, the predominant human fungal pathogen, thrives under diverse environments with vastly different iron levels in the mammalian host. Therefore, to tightly control iron homeostasis, C. albicans has evolved a set of transcriptional regulators that cooperate to either upregulate or downregulate transcription of iron uptake genes or iron utilization genes. Cap2/Hap43, a critical transcriptional regulator, contains multiple conserved protein domains. In this study, we carried out mutational analyses to identify the functional roles of the conserved protein domains in Cap2. Our results show that the bZIP, HAP4L, and the C-terminal domain are each required for Cap2 transcriptional activity. Thus, Cap2 employs multiple, disparate protein domains for regulation of iron homeostasis in C. albicans.
- Published
- 2018
44. Novel Regulators of Melanogenesis Identified by Genome‐wide Transcriptome Analysis
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Krishnamurthy Natarajan, Chetan Gadgil, Mudita Shukla, Vivek T. Natarajan, Kritika Kirty, Shalini Yadav, and Rajesh S. Gokhale
- Subjects
Transcriptome ,Genetics ,Computational biology ,Biology ,Molecular Biology ,Biochemistry ,Genome ,Biotechnology - Published
- 2018
45. Biochemical characterization of
- Author
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Shweta, Sharma, Gautam, Kumar, Mohit, Vashishta, Rajan, Pandey, Sumit, Rathore, Bishwanath K, Chourasia, Jhalak, Singhal, Arunaditya, Deshmukh, Md, Kalamuddin, Gourab, Paul, Ashutosh, Panda, Shreyansh, Tatiya, Khushboo, Rawat, Dinesh, Gupta, Asif, Mohmmed, Krishnamurthy, Natarajan, and Pawan, Malhotra
- Subjects
Mice ,Mice, Inbred BALB C ,Plasmodium berghei ,Plasmodium falciparum ,Protozoan Proteins ,Animals ,Humans ,Immunologic Factors ,Immunization ,Dendritic Cells ,Toll-Like Receptor 2 ,Signal Transduction - Abstract
Complement system is the first line of human defence against intruding pathogens and is recognized as a potentially useful therapeutic target. Human malaria parasite
- Published
- 2018
46. Suppressive role of neddylation in dendritic cells during Mycobacterium tuberculosis infection
- Author
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Mohit Vashishta, Sonam Popli, Krishnamurthy Natarajan, Rajagopal Raman, Yogendra Singh, Subhash Mehto, Arti Selvakumar, Shashank S. Kamble, and Attinder Chadha
- Subjects
Microbiology (medical) ,NEDD8 Protein ,Immunology ,Cellular homeostasis ,Apoptosis ,Biology ,Transfection ,Microbiology ,Phagolysosome ,NEDD8 ,Immune system ,Phagocytosis ,Antigen ,Autophagy ,Animals ,Tuberculosis ,Calcium Signaling ,Ubiquitins ,Cells, Cultured ,Respiratory Burst ,Phagosome-lysosome fusion ,Antigens, Bacterial ,Mice, Inbred BALB C ,Toll-Like Receptors ,Ubiquitination ,Dendritic Cells ,Mycobacterium tuberculosis ,Cullin Proteins ,Cell biology ,Infectious Diseases ,Host-Pathogen Interactions ,Female ,RNA Interference ,Neddylation ,Mitogen-Activated Protein Kinases ,Protein Processing, Post-Translational - Abstract
Multiple strategies evolved by Mycobacterium tuberculosis (M. tb) have contributed to its successful prevalence. We previously identified specific genes in the cysteine protease and calcium-calmodulin pathways that regulated immune responses from dendritic cells (DCs). In this study we have characterized the role of neddylation in regulating various defense responses from DCs during mycobacterial infection. Neddylation is a process that is similar to ubiquitination. It however has its own enzyme machinery. It is coupled to ubiquitination and is important for maintaining cellular homeostasis. Here we show that stimulation of DCs with M. tb antigens Rv2463 and Rv3416 as well as infection with live M. tb modulates the expression levels of key proteins in the neddylation pathway. Further, stimulation with the two antigens promoted the association of NEDD8 with its target Cullin-1. The modulation in the expression levels of NEDD8 and SENtrin specific Protein 8 (SENP8) by the two antigens was in a calcium, MAPK and TLR dependent mechanism. Further, knockdown of specific genes of neddylation promoted the generation of oxidative burst, promoted phagolysosome fusion in mycobacteria infected DCs and induced higher expression of autophagy and apoptosis associated proteins in DCs. These results point toward a unique strategy employed by mycobacteria and its antigens towards immune suppression via modulating neddylation in DCs.
- Published
- 2015
47. Correction for Saint et al., 'The TAF9 C-Terminal Conserved Region Domain Is Required for SAGA and TFIID Promoter Occupancy To Promote Transcriptional Activation'
- Author
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Rahul Siddharthan, Krishnamurthy Natarajan, Anushikha Thakur, Rashmi Dahiya, Sonal Sawhney, Ishani Sinha, Malika Saint, and Rana P. Singh
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Genetics ,Terminal (electronics) ,TAF9 ,macromolecular substances ,Articles ,Cell Biology ,Computational biology ,Transcription factor II D ,Biology ,Molecular Biology ,eye diseases ,Domain (software engineering) - Abstract
A common function of the TFIID and SAGA complexes, which are recruited by transcriptional activators, is to deliver TBP to promoters to stimulate transcription. Neither the relative contributions of the five shared TBP-associated factor (TAF) subunits in TFIID and SAGA nor the requirement for different domains in shared TAFs for transcriptional activation is well understood. In this study, we uncovered the essential requirement for the highly conserved C-terminal region (CRD) of Taf9, a shared TAF, for transcriptional activation in yeast. Transcriptome profiling performed under Gcn4-activating conditions showed that the Taf9 CRD is required for induced expression of ∼9% of the yeast genome. The CRD was not essential for the Taf9-Taf6 interaction, TFIID or SAGA integrity, or Gcn4 interaction with SAGA in cell extracts. Microarray profiling of a SAGA mutant (spt20Δ) yielded a common set of genes induced by Spt20 and the Taf9 CRD. Chromatin immunoprecipitation (ChIP) assays showed that, although the Taf9 CRD mutation did not impair Gcn4 occupancy, the occupancies of TFIID, SAGA, and the preinitiation complex were severely impaired at several promoters. These results suggest a crucial role for the Taf9 CRD in genome-wide transcription and highlight the importance of conserved domains, other than histone fold domains, as a common determinant for TFIID and SAGA functions.
- Published
- 2017
48. Mapping architectural and transcriptional alterations in non-lesional and lesional epidermis in vitiligo
- Author
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Riitta Lahesmaa, Chetan Gadgil, Hemanta Kumar Kar, Vinaya Vijayan, Avinash Kumar, Tanveer Fatima, Manisha Tiwari, Pankaj Sharma, Parul Ganju, Lipi Thukral, Sangeeta Khanna, Päivi Junni, Archana Singh, Krishnamurthy Natarajan, Vishvabandhu Gotherwal, Rajesh S. Gokhale, Garima Malik, Rajni Rani, Vivek T. Natarajan, Ananthaprasad Holla, and Aayush Gupta
- Subjects
0301 basic medicine ,Adult ,Male ,Vitiligo ,lcsh:Medicine ,Biology ,Article ,Transcriptome ,Melanin ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Stratum corneum ,Humans ,Gene Regulatory Networks ,lcsh:Science ,Tissue homeostasis ,Multidisciplinary ,Corneocyte ,Epidermis (botany) ,integumentary system ,Gene Expression Profiling ,lcsh:R ,Computational Biology ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,lcsh:Q ,Female ,Disease Susceptibility ,Epidermis ,Biomarkers - Abstract
In vitiligo, chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance. The stable vitiligo patches are known to attain an irreversible depigmented state. However, the molecular and cellular processes resulting in this remodeled tissue homeostasis is unclear. To investigate the complex interplay of inductive signals and cell intrinsic factors that support the new acquired state, we compared the matched lesional and non-lesional epidermis obtained from stable non-segmental vitiligo subjects. Hierarchical clustering of genome-wide expression of transcripts surprisingly segregated lesional and non-lesional samples in two distinct clades, despite the apparent heterogeneity in the lesions of different vitiligo subjects. Pathway enrichment showed the expected downregulation of melanogenic pathway and a significant downregulation of cornification and keratinocyte differentiation processes. These perturbations could indeed be recapitulated in the lesional epidermal tissue, including blunting of rete-ridges, thickening of stratum corneum and increase in the size of corneocytes. In addition, we identify marked increase in the putrescine levels due to the elevated expression of spermine/spermidine acetyl transferase. Our study provides insights into the intrinsic self-renewing ability of damaged lesional tissue to restore epidermal functionality in vitiligo.
- Published
- 2017
49. Suppression of Toll-like receptor 2-mediated proinflammatory responses by
- Author
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Upasana, Bandyopadhyay, Attinder, Chadha, Priya, Gupta, Brijendra, Tiwari, Kausik, Bhattacharyya, Sonam, Popli, Rajagopal, Raman, Vani, Brahamachari, Yogendra, Singh, Pawan, Malhotra, and Krishnamurthy, Natarajan
- Subjects
Primary Cell Culture ,Membrane Fusion ,Interferon-gamma ,Mice ,Bacterial Proteins ,Protein Domains ,Transforming Growth Factor beta ,Phagosomes ,Animals ,Immune Evasion ,Respiratory Burst ,Mitogen-Activated Protein Kinase Kinases ,Interleukin-6 ,Macrophages ,Interleukin-17 ,Molecular Mimicry ,NF-kappa B ,Mycobacterium tuberculosis ,Bacterial Load ,Toll-Like Receptor 2 ,Interleukin-10 ,Interleukin-1 Receptor-Associated Kinases ,Gene Expression Regulation ,Myeloid Differentiation Factor 88 ,Lysosomes ,Signal Transduction - Abstract
Microorganisms are known to devise various strategies to thwart protective responses by the host. One such strategy is to incorporate sequences and domains in their genes/proteins that have similarity to various domains of the host proteins. In this study, we report that
- Published
- 2017
50. Iron Acquisition in the Pathobiology of Candida albicans
- Author
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Manjit Kumar Srivastav, Remya Nair, and Krishnamurthy Natarajan
- Subjects
0301 basic medicine ,biology ,030106 microbiology ,Virulence ,Human pathogen ,biology.organism_classification ,Phenotype ,Corpus albicans ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,Immunity ,Transcriptional regulation ,Candida albicans ,Gene - Abstract
The host nutritional environment is a key determinant for survival of human pathogens including C. albicans. Iron is an essential micronutrient for the host as well as for C. albicans. However, iron sequestration in host proteins confers ‘nutritional immunity’. In this chapter, we have reviewed our current understanding of the different iron uptake systems, the associated genes, and their transcriptional regulation in C. albicans. Besides, iron acquisition is essential for C. albicans virulence and iron homeostasis is also interlinked with lipid homeostasis and multidrug resistance. We have also provided an atlas of all annotated C. albicans iron acquisition genes with the attendant gene expression, and phenotype data including virulence.
- Published
- 2017
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