5 results on '"Rashmi, Godbole"'
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2. Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors
- Author
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Akshatha Shivaraj, Dhruv Sheth, Thomas S. van Zanten, Satyajit Mayor, Varadharajan Sundaramurthy, Shah-e-Jahan Gulzar, Bhagyashri Mahajan, Neeraja Subhash, Parvinder Pal Singh, Sandip B. Bharate, Theja Parassini Puthiyapurayil, Arjun Guha, Praveen Kumar Vemula, Ibrahim U, Ram A. Vishwakarma, Riyaz Ahmed, Parijat Sil, Ashaq Hussain Najar, Sowmya Jahnavi, Vijay K. Nuthakki, Patricia Panikulam, Sai Manoz Lingamallu, Chaitra Prabhakara, Rashmi Godbole, Snigdhadev Das, and Anchal Chandra
- Subjects
0301 basic medicine ,RNA viruses ,Coronaviruses ,Cell Lines ,Endocytic cycle ,Glycobiology ,Biochemistry ,0302 clinical medicine ,Chlorocebus aethiops ,Biology (General) ,Glucans ,Pathology and laboratory medicine ,Secretory Pathway ,Chemistry ,Drugs ,Chloroquine ,Drug Synergism ,Hydrogen-Ion Concentration ,Medical microbiology ,Endocytosis ,Cell biology ,Cell Processes ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,Viruses ,Niclosamide ,Angiotensin-Converting Enzyme 2 ,Macrolides ,Biological Cultures ,Cellular Structures and Organelles ,SARS CoV 2 ,Pathogens ,medicine.drug ,Hydroxychloroquine ,Protein Binding ,Research Article ,Viral Entry ,SARS coronavirus ,Endosome ,QH301-705.5 ,Immunology ,Endosomes ,Research and Analysis Methods ,Antiviral Agents ,Microbiology ,Ammonium Chloride ,Cell Line ,03 medical and health sciences ,Antimalarials ,Protein Domains ,Viral entry ,Polysaccharides ,Virology ,Genetics ,medicine ,Animals ,Humans ,Vesicles ,Molecular Biology ,Vero Cells ,Dextran ,Medicine and health sciences ,Pharmacology ,SARS-CoV-2 ,Host Cells ,Organisms ,Viral pathogens ,COVID-19 ,Biology and Life Sciences ,Cell Biology ,RC581-607 ,Virus Internalization ,Clathrin ,Entry inhibitor ,COVID-19 Drug Treatment ,Microbial pathogens ,030104 developmental biology ,Cell culture ,Vero cell ,Parasitology ,Ectopic expression ,Immunologic diseases. Allergy ,Viral Transmission and Infection - Abstract
Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway., Author summary This study investigates the cellular mechanisms by which SARS-CoV-2 can gain entry into human cells. We find that the virus employs diverse endocytic processes to enter cells and the acidic environment within these endocytic compartments is essential for infection. Using these observations from first principles, we screened a small set of FDA-approved drugs which could potentially inhibit endosomal acidification and therefore prevent viral entry and infection. The routinely prescribed anti-helminthic drug, Niclosamide, was observed to have this capability. Our study proposes that drugs altering both endocytic entry as well as endosomal acidification can assist in the clinical management of viral infections.
- Published
- 2021
3. Niclosamide inhibits SARS-CoV2 entry by blocking internalization through pH-dependent CLIC/GEEC endocytic pathway
- Author
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Varadharajan Sundaramurthy, Vijay K. Nuthakki, Riyaz Ahmed, Sai Manoz Lingamallu, Arjun Guha, Bhagyashri Mahajan, Praveen Kumar Vemula, Ashaq Hussain Najar, Neeraja Subhash, Thomas S. van Zanten, Sowmya Jahnavi, Chaitra Prabhakara, Parvinder Pal Singh, Rashmi Godbole, Parijat Sil, Snigdhadev Das, Ram A. Vishwakarma, Sandip B. Bharate, Dhruv Sheth, Satyajit Mayor, Theja Parassini Puthiyapurayil, and Anchal Chandra
- Subjects
biology ,Chemistry ,Endosome ,media_common.quotation_subject ,Endocytic cycle ,Clathrin ,Cell biology ,Entry inhibitor ,Transduction (genetics) ,Chloroquine ,biology.protein ,medicine ,Internalization ,Niclosamide ,medicine.drug ,media_common - Abstract
Many viruses utilize the host endo-lysosomal network to infect cells. Tracing the endocytic itinerary of SARS-CoV2 can provide insights into viral trafficking and aid in designing new therapeutic targets. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV2 is internalized via the clathrin and dynamin-independent, pH-dependent CLIC/GEEC (CG) endocytic pathway. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, strongly block the uptake of RBD. Using transduction assays with SARS-CoV2 Spike-pseudovirus, we confirmed that these acidification inhibitors also impede viral infection. By contrast, Chloroquine neither affects RBD uptake nor extensively alters the endosomal pH, yet attenuates Spike-pseudovirus entry, indicating a pH-independent mechanism of intervention. We screened a subset of FDA-approved acidification inhibitors and found Niclosamide to be a potential SARS-CoV2 entry inhibitor. Niclosamide, thus, could provide broader applicability in subverting infection of similar category viruses entering host cells via this pH-dependent endocytic pathway.
- Published
- 2020
4. Cargo-specific recruitment in clathrin and dynamin-independent endocytosis
- Author
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Christian Sommer, Roosa E. Kallionpää, Satyajit Mayor, Stefan Linder, Stefan Veltel, Guillaume Jacquemet, Pauliina Kronqvist, Johanna Ivaska, Pasquale Cervero, Paulina Moreno-Layseca, James Rae, Martin Aepfelbacher, Niklas Z. Jäntti, Giorgio Scita, Hussein Al-Akhrass, Robert G. Parton, Andrea Disanza, Matthias Selbach, Rashmi Godbole, and Leticia Oliveira-Ferrer
- Subjects
biology ,Chemistry ,media_common.quotation_subject ,Endocytic cycle ,Integrin ,Endocytosis ,Clathrin ,Cell biology ,biology.protein ,Internalization ,Actin ,Tissue homeostasis ,Dynamin ,media_common - Abstract
Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis, and cancer invasion and is often hijacked by viral infections 1. Unlike clathrin-mediated endocytosis, which exploits cargo-specific adaptors for selective protein internalization, the clathrin and dynamin-independent endocytic pathway (CLIC-GEEC, CG-pathway) has until now been considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids 2,3. Although the core molecular players of CG endocytosis have been recently defined, no cargo-specific adaptors are known and evidence of selective protein uptake into the pathway is lacking 3. Here, we identify the first cargo-specific adaptor for CG-endocytosis and demonstrate its clinical relevance in breast cancer progression. By combining unbiased molecular characterization and super-resolution imaging, we identified the actin-binding protein swiprosin-1 (EFHD2) as a cargo-specific adaptor regulating integrin internalization via the CG-pathway. Swiprosin-1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery, IRSp53 and actin. Swiprosin-1 is critical for integrin endocytosis, but not for other CG-cargo and supports integrin-dependent cancer cell migration and invasion, with clinically relevant implications for breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG-pathway and opens the possibility to discover more adaptors regulating it.
- Published
- 2020
5. Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis
- Author
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Paulina, Moreno-Layseca, Niklas Z, Jäntti, Rashmi, Godbole, Christian, Sommer, Guillaume, Jacquemet, Hussein, Al-Akhrass, James R W, Conway, Pauliina, Kronqvist, Roosa E, Kallionpää, Leticia, Oliveira-Ferrer, Pasquale, Cervero, Stefan, Linder, Martin, Aepfelbacher, Henrik, Zauber, James, Rae, Robert G, Parton, Andrea, Disanza, Giorgio, Scita, Satyajit, Mayor, Matthias, Selbach, Stefan, Veltel, and Johanna, Ivaska
- Subjects
Dynamins ,Cell Movement ,rab GTP-Binding Proteins ,Integrin beta1 ,Intracellular Signaling Peptides and Proteins ,Humans ,Biological Transport ,Breast Neoplasms ,Female ,Actins ,Clathrin ,Endocytosis - Abstract
Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route.
- Published
- 2020
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