248 results on '"Savidor A"'
Search Results
2. Loss of EIF4G2 mediates aggressiveness in distinct human endometrial cancer subpopulations with poor survival outcome in patients
- Author
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Meril, Sara, Muhlbauer Avni, Maya, Lior, Chen, Bahlsen, Marcela, Olender, Tsviya, Savidor, Alon, Krausz, Judit, Belhanes Peled, Hila, Birisi, Hila, David, Nofar, Bialik, Shani, Scherz-Shouval, Ruth, Ben David, Yehuda, and Kimchi, Adi
- Published
- 2024
- Full Text
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3. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury
- Author
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Shakked, Avraham, Petrover, Zachary, Aharonov, Alla, Ghiringhelli, Matteo, Umansky, Kfir-Baruch, Kain, David, Elkahal, Jacob, Divinsky, Yalin, Nguyen, Phong Dang, Miyara, Shoval, Friedlander, Gilgi, Savidor, Alon, Zhang, Lingling, Perez, Dahlia E., Sarig, Rachel, Lendengolts, Daria, Bueno-Levy, Hanna, Kastan, Nathaniel, Levin, Yishai, Bakkers, Jeroen, Gepstein, Lior, and Tzahor, Eldad
- Published
- 2023
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4. A new function for the serine protease HtrA2 in controlling radiation‐induced senescence in cancer cells
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Liat Hammer, Vered Levin‐Salomon, Naama Yaeli‐Slonim, Moria Weiss, Naama P. Dekel‐Bird, Tsviya Olender, Ziv Porat, Sabina Winograd‐Katz, Alon Savidor, Yishai Levin, Shani Bialik, Benjamin Geiger, and Adi Kimchi
- Subjects
cellular senescence ,HtrA2/Omi ,radiation therapy ,siRNA functional screen ,vimentin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Radiation therapy can induce cellular senescence in cancer cells, leading to short‐term tumor growth arrest but increased long‐term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation‐induced senescence in cultured cancer cells. The irradiated cells exhibited a typical senescent phenotype, including upregulation of p53 and its main target, p21, followed by a sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence‐associated beta‐galactosidase activity. Mass spectrometry‐based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy. A functional siRNA screen using a cell death‐related library identified mitochondrial serine protease HtrA2 as being necessary for sustained growth arrest of the senescent cells. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus, HtrA2 is involved in the cytoskeletal reorganization that accompanies radiation‐induced senescence and the continuous maintenance of proliferation arrest.
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- 2022
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5. Spatial discordances between mRNAs and proteins in the intestinal epithelium
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Harnik, Yotam, Buchauer, Lisa, Ben-Moshe, Shani, Averbukh, Inna, Levin, Yishai, Savidor, Alon, Eilam, Raya, Moor, Andreas E., and Itzkovitz, Shalev
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- 2021
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6. Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease
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Karlinski Zur, Maayan, primary, Bhattacharya, Bidisha, additional, Ben Dor, Sivan, additional, Solomonov, Inna, additional, Savidor, Alon, additional, Sapir, Tamar, additional, Harris, Talia, additional, Olender, Tsviya, additional, Sagi, Irit, additional, Schmidt, Rita, additional, Schwarz, Jen, additional, Buxboim, Amnon, additional, and Reiner, Orly, additional
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- 2024
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7. Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor
- Author
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Meril, Sara, primary, Bahlsen, Marcela, additional, Eisenstein, Miriam, additional, Savidor, Alon, additional, Levin, Yishai, additional, Bialik, Shani, additional, Pietrokovski, Shmuel, additional, and Kimchi, Adi, additional
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- 2023
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8. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration
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Aharonov, Alla, Shakked, Avraham, Umansky, Kfir Baruch, Savidor, Alon, Genzelinakh, Alexander, Kain, David, Lendengolts, Daria, Revach, Or-Yam, Morikawa, Yuka, Dong, Jixin, Levin, Yishai, Geiger, Benjamin, Martin, James F., and Tzahor, Eldad
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- 2020
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9. Dysregulated miRNA biogenesis downstream of cellular stress and ALS‐causing mutations: a new mechanism for ALS
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Emde, Anna, Eitan, Chen, Liou, Lee-Loung, Libby, Ryan T, Rivkin, Natali, Magen, Iddo, Reichenstein, Irit, Oppenheim, Hagar, Eilam, Raya, Silvestroni, Aurelio, Alajajian, Betty, Ben-Dov, Iddo Z, Aebischer, Julianne, Savidor, Alon, Levin, Yishai, Sons, Robert, Hammond, Scott M, Ravits, John M, Möller, Thomas, and Hornstein, Eran
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Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Biotechnology ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Rare Diseases ,ALS ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Amyotrophic Lateral Sclerosis ,Animals ,Base Sequence ,Cytoplasmic Granules ,DEAD-box RNA Helicases ,Down-Regulation ,Drug Evaluation ,Preclinical ,Enoxacin ,Female ,HEK293 Cells ,Humans ,Male ,Mice ,Inbred C57BL ,Mice ,Transgenic ,MicroRNAs ,Motor Neurons ,RNA Interference ,RNA Processing ,Post-Transcriptional ,Ribonuclease III ,Stress ,Physiological ,Superoxide Dismutase ,Superoxide Dismutase-1 ,microRNA ,stress ,neurodegeneration ,DICER ,Information and Computing Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.
- Published
- 2015
10. Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor.
- Author
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Meril, Sara, Bahlsen, Marcela, Eisenstein, Miriam, Savidor, Alon, Levin, Yishai, Bialik, Shani, Pietrokovski, Shmuel, and Kimchi, Adi
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- 2024
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11. Loss of EIF4G2 Mediates Aggressiveness in Distinct Human Endometrial Cancer Subpopulations with Poorer Survival Outcome in Patients
- Author
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Meril, Sara, primary, Muhlbauer Avni, Maya, additional, Lior, Chen, additional, Bhalsen, Marcela, additional, Olender, Tsviya, additional, Savidor, Alon, additional, Krausz, Judit, additional, Belhanes Peled, Hila, additional, Birisi, Hila, additional, David, Nofar, additional, Bialik, Shani, additional, Scherz-Shouval, Ruth, additional, Ben David, Yehuda, additional, and Kimchi, Adi, additional
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- 2023
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12. Loss-of-function cancer-associated mutations in the EIF4G2 non-canonical translation initiation factor
- Author
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Meril, Sara, primary, Bhalsen, Marcela, additional, Eisenstein, Miriam, additional, Savidor, Alon, additional, Levin, Yishai, additional, Bialik, Shani, additional, Pietrokovski, Shmuel, additional, and Kimchi, Adi, additional
- Published
- 2023
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13. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury
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Avraham Shakked, Zachary Petrover, Alla Aharonov, Matteo Ghiringhelli, Kfir-Baruch Umansky, David Kain, Jacob Elkahal, Yalin Divinsky, Phong Dang Nguyen, Shoval Miyara, Gilgi Friedlander, Alon Savidor, Lingling Zhang, Dahlia E. Perez, Rachel Sarig, Daria Lendengolts, Hanna Bueno-Levy, Nathaniel Kastan, Yishai Levin, Jeroen Bakkers, Lior Gepstein, and Eldad Tzahor
- Published
- 2023
14. Genome Sequencing and Mapping Reveal Loss of Heterozygosity as a Mechanism for Rapid Adaptation in the Vegetable Pathogen Phytophthora capsici
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Lamour, Kurt H., Mudge, Joann, Gobena, Daniel, Hurtado-Gonzales, Oscar P., Schmutz, Jeremy, Kuo, Alan, Miller, Neil A., Rice, Brandon J., Raffaele, Sylvain, Cano, Liliana M., Bharti, Arvind K., Donahoo, Ryan S., Finely, Sabra, Huitema, Edgar, Hulvey, Jon, Platt, Darren, Salamov, Asaf, Savidor, Alon, Sharma, Rahul, Stam, Remco, Sotrey, Dylan, Thines, Marco, Win, Joe, Haas, Brian J., Dinwiddie, Darrell L., Jenkins, Jerry, Knight, James R., Affourtit, Jason P., Han, Cliff S., Chertkov, Olga, Lindquist, Erika A., Detter, Chris, Grigoriev, Igor V., Kamoun, Sophien, and Kingsmore, Stephen F.
- Abstract
The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30percent of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.
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- 2012
15. Phytophthora Genome Sequences Uncover Evolutionary Origins and Mechanisms of Pathogenesis
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Tyler, Brett M., Tripathy, Sucheta, Zhang, Xuemin, Dehal, Paramvir, Aerts, Andrea, Arredondo, Felipe D., Baxter, Laura, Bensasson, Douda, Beynon, Jim L., Chapman, Jarrod, Dorrance, Anne E., Dou, Daolong, Dickerman, Allan W., Dubchak, Inna L., Garbelotto, Matteo, Gijzen, Mark, Gordon, Stuart G., Govers, Francine, Grunwald, Niklaus J., Huang, Wayne, Ivors, Kelly L., Jones, Richard W., Kamoun, Sophien, Krampis, Konstantinos, Lamour, Kurt H., Lee, Mi-Kyung, McDonald, W. Hayes, Medina, Mónica, Nordberg, Eric K., Maclean, Donald J., Ospina-Giraldo, Manuel D., Morris, Paul F., Phuntumart, Vipaporn, Putnam, Nicholas H., Rash, Sam, Sakihama, Yasuko, Salamov, Asaf A., Savidor, Alon, Scheuring, Chantel F., Smith, Brian M., Terry, Astrid, Torto-Alalibo, Trudy A., Win, Joe, Xu, Zhanyou, Zhang, Hongbin, Grigoriev, Igor V., Rokhsar, Daniel S., and Boore, Jeffrey L.
- Published
- 2006
16. Loss of the Periplasmic Chaperone Skp and Mutations in the Efflux Pump AcrAB-TolC Play a Role in Acquired Resistance to Antimicrobial Peptides in Salmonella typhimurium
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Gal Kapach, Reut Nuri, Christiane Schmidt, Adi Danin, Shir Ferrera, Alon Savidor, Roman G. Gerlach, and Yechiel Shai
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antimicrobial peptide (AMPs) ,bacterial resistance ,AcrAB-TolC ,ramR ,Skp ,periplasm ,Microbiology ,QR1-502 - Abstract
Bacterial resistance to antibiotics is a major concern worldwide, leading to an extensive search for alternative drugs. Promising candidates are antimicrobial peptides (AMPs), innate immunity molecules, shown to be highly efficient against multidrug resistant bacteria. Therefore, it is essential to study bacterial resistance mechanisms against them. For that purpose, we used experimental evolution, and isolated a Salmonella enterica serovar typhimurium-resistant line to the AMP 4DK5L7. This AMP displayed promising features including widespread activity against Gram-negative bacteria and protection from proteolytic degradation. However, the resistance that evolved in the isolated strain was particularly high. Whole genome sequencing revealed that five spontaneous mutations had evolved. Of these, three are novel in the context of acquired AMP resistance. Two mutations are related to the AcrAB-TolC multidrug efflux pump. One occurred in AcrB, the substrate-binding domain of the system, and the second in RamR, a transcriptional regulator of the system. Together, the mutations increased the minimal inhibitory concentration (MIC) by twofold toward this AMP. Moreover, the mutation in AcrB induced hypersusceptibility toward ampicillin and colistin. The last mutation occurred in Skp, a periplasmic chaperone that participates in the biogenesis of outer membrane proteins (OMPs). This mutation increased the MIC by twofold to 4DK5L7 and by fourfold to another AMP, seg5D. Proteomic analysis revealed that the mutation abolished Skp expression, reduced OMP abundance, and increased DegP levels. DegP, a protease that was reported to have an additional chaperone activity, escorts OMPs through the periplasm along with Skp, but is also associated with AMP resistance. In conclusion, our data demonstrate that both loss of Skp and manipulation of the AcrAB-TolC system are alternative strategies of AMP acquired resistance in Salmonella typhimurium and might represent a common mechanism in other Gram-negative bacteria.
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- 2020
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17. BcXYG1, a Secreted Xyloglucanase from Botrytis cinerea , Triggers Both Cell Death and Plant Immune Responses
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Zhu, Wenjun, Ronen, Mordechi, Gur, Yonatan, Minz-Dub, Anna, Masrati, Gal, Ben-Tal, Nir, Savidor, Alon, Sharon, Itai, Eizner, Elad, Valerius, Oliver, Braus, Gerhard H., Bowler, Kyle, Bar-Peled, Maor, and Sharon, Amir
- Published
- 2017
18. The genetic basis for the adaptation of E. coli to sugar synthesis from CO2
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Elad Herz, Niv Antonovsky, Yinon Bar-On, Dan Davidi, Shmuel Gleizer, Noam Prywes, Lianet Noda-Garcia, Keren Lyn Frisch, Yehudit Zohar, David G. Wernick, Alon Savidor, Uri Barenholz, and Ron Milo
- Subjects
Science - Abstract
An E. coli strain able to use CO2 fixation for sugar synthesis was previously generated by experimental evolution of an engineered strain. Here, Herz et al. show that specific mutations in five genes, encoding carbon metabolism enzymes or key regulators, are sufficient to enable robust growth of the strain.
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- 2017
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19. BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures
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Danino, Yehuda M, primary, Molitor, Lena, additional, Rosenbaum-Cohen, Tamar, additional, Kaiser, Sebastian, additional, Cohen, Yahel, additional, Porat, Ziv, additional, Marmor-Kollet, Hagai, additional, Katina, Corine, additional, Savidor, Alon, additional, Rotkopf, Ron, additional, Ben-Isaac, Eyal, additional, Golani, Ofra, additional, Levin, Yishai, additional, Monchaud, David, additional, Hickson, Ian D, additional, and Hornstein, Eran, additional
- Published
- 2023
- Full Text
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20. SPEAR: A proteomics approach for simultaneous protein expression and redox analysis
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Doron, Shani, primary, Lampl, Nardy, additional, Savidor, Alon, additional, Katina, Corine, additional, Gabashvili, Alexandra, additional, Levin, Yishai, additional, and Rosenwasser, Shilo, additional
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- 2023
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21. BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures
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Danino, Yehuda M., Molitor, Lena, Rosenbaum-Cohen, Tamar, Kaiser, Sebastian, Cohen, Yahel, Porat, Ziv, Marmor-Kollet, Hagai, Katina, Corine, Savidor, Alon, Rotkopf, Ron, Ben-Isaac, Eyal, Golani, Ofra, Levin, Yishai, Monchaud, David, Hickson, Ian D., Hornstein, Eran, Danino, Yehuda M., Molitor, Lena, Rosenbaum-Cohen, Tamar, Kaiser, Sebastian, Cohen, Yahel, Porat, Ziv, Marmor-Kollet, Hagai, Katina, Corine, Savidor, Alon, Rotkopf, Ron, Ben-Isaac, Eyal, Golani, Ofra, Levin, Yishai, Monchaud, David, Hickson, Ian D., and Hornstein, Eran
- Abstract
Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.
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- 2023
22. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury
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Cardiologie onderzoek 2, Onderzoek, Child Health, Circulatory Health, Shakked, Avraham, Petrover, Zachary, Aharonov, Alla, Ghiringhelli, Matteo, Umansky, Kfir Baruch, Kain, David, Elkahal, Jacob, Divinsky, Yalin, Nguyen, Phong Dang, Miyara, Shoval, Friedlander, Gilgi, Savidor, Alon, Zhang, Lingling, Perez, Dahlia E., Sarig, Rachel, Lendengolts, Daria, Bueno-Levy, Hanna, Kastan, Nathaniel, Levin, Yishai, Bakkers, Jeroen, Gepstein, Lior, Tzahor, Eldad, Cardiologie onderzoek 2, Onderzoek, Child Health, Circulatory Health, Shakked, Avraham, Petrover, Zachary, Aharonov, Alla, Ghiringhelli, Matteo, Umansky, Kfir Baruch, Kain, David, Elkahal, Jacob, Divinsky, Yalin, Nguyen, Phong Dang, Miyara, Shoval, Friedlander, Gilgi, Savidor, Alon, Zhang, Lingling, Perez, Dahlia E., Sarig, Rachel, Lendengolts, Daria, Bueno-Levy, Hanna, Kastan, Nathaniel, Levin, Yishai, Bakkers, Jeroen, Gepstein, Lior, and Tzahor, Eldad
- Published
- 2023
23. The Chloroplast Envelope Protease FTSH11 – Interaction With CPN60 and Identification of Potential Substrates
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Zach Adam, Elinor Aviv-Sharon, Alona Keren-Paz, Leah Naveh, Mor Rozenberg, Alon Savidor, and Junping Chen
- Subjects
FTSH11 ,chloroplast ,envelope ,proteolysis ,AAA protease ,CPN60 ,Plant culture ,SB1-1110 - Abstract
FTSH proteases are membrane-bound, ATP-dependent metalloproteases found in bacteria, mitochondria and chloroplasts. The product of one of the 12 genes encoding FTSH proteases in Arabidopsis, FTSH11, has been previously shown to be essential for acquired thermotolerance. However, the substrates of this protease, as well as the mechanism linking it to thermotolerance are largely unknown. To get insight into these, the FTSH11 knockout mutant was complemented with proteolytically active or inactive variants of this protease, tagged with HA-tag, under the control of the native promoter. Using these plants in thermotolerance assay demonstrated that the proteolytic activity, and not only the ATPase one, is essential for conferring thermotolerance. Immunoblot analyses of leaf extracts, isolated organelles and sub-fractionated chloroplast membranes localized FTSH11 mostly to chloroplast envelopes. Affinity purification followed by mass spectrometry analysis revealed interaction between FTSH11 and different components of the CPN60 chaperonin. In affinity enrichment assays, CPN60s as well as a number of envelope, stroma and thylakoid proteins were found associated with proteolytically inactive FTSH11. Comparative proteomic analysis of WT and knockout plants, grown at 20°C or exposed to 30°C for 6 h, revealed a plethora of upregulated chloroplast proteins in the knockout, some of them might be candidate substrates. Among these stood out TIC40, which was stabilized in the knockout line after recovery from heat stress, and three proteins that were found trapped in the affinity enrichment assay: the nucleotide antiporter PAPST2, the fatty acid binding protein FAP1 and the chaperone HSP70. The consistent behavior of these four proteins in different assays suggest that they are potential FTSH11 substrates.
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- 2019
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24. Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling
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Levy, Maayan, Thaiss, Christoph A., Zeevi, David, Dohnalová, Lenka, Zilberman-Schapira, Gili, Mahdi, Jemal Ali, David, Eyal, Savidor, Alon, Korem, Tal, Herzig, Yonatan, Pevsner-Fischer, Meirav, Shapiro, Hagit, Christ, Anette, Harmelin, Alon, Halpern, Zamir, Latz, Eicke, Flavell, Richard A., Amit, Ido, Segal, Eran, and Elinav, Eran
- Published
- 2015
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25. Spatial discordances between mRNAs and proteins in the intestinal epithelium
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Yotam Harnik, Lisa Buchauer, Shani Ben-Moshe, Inna Averbukh, Yishai Levin, Alon Savidor, Raya Eilam, Andreas E. Moor, and Shalev Itzkovitz
- Subjects
Male ,Proteomics ,Proteome ,Protein Stability ,Gene Expression Profiling ,RNA Stability ,Endocrinology, Diabetes and Metabolism ,Cell Biology ,Immunohistochemistry ,Mice ,Enterocytes ,Gene Expression Regulation ,Physiology (medical) ,Internal Medicine ,Animals ,Intestinal Mucosa ,Transcriptome - Abstract
The use of transcriptomes as reliable proxies for cellular proteomes is controversial. In the small intestine, enterocytes operate for 4 days as they migrate along villi, which are highly graded microenvironments. Spatial transcriptomics have demonstrated profound zonation in enterocyte gene expression, but how this variability translates to protein content is unclear. Here we show that enterocyte proteins and messenger RNAs along the villus axis are zonated, yet often spatially discordant. Using spatial sorting with zonated surface markers, together with a Bayesian approach to infer protein translation and degradation rates from the combined spatial profiles, we find that, while many genes exhibit proteins zonated toward the villus tip, mRNA is zonated toward the villus bottom. Finally, we demonstrate that space-independent protein synthesis delays can explain many of the mRNA-protein discordances. Our work provides a proteomic spatial blueprint of the intestinal epithelium, highlighting the importance of protein measurements for inferring cell states in tissues that operate outside of steady state.
- Published
- 2021
26. The Xanthomonas euvesicatoria type III effector XopAU is an active protein kinase that manipulates plant MAP kinase signaling.
- Author
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Doron Teper, Anil Madhusoodana Girija, Eran Bosis, Georgy Popov, Alon Savidor, and Guido Sessa
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The Gram-negative bacterium Xanthomonas euvesicatoria (Xe) is the causal agent of bacterial spot disease of pepper and tomato. Xe delivers effector proteins into host cells through the type III secretion system to promote disease. Here, we show that the Xe effector XopAU, which is conserved in numerous Xanthomonas species, is a catalytically active protein kinase and contributes to the development of disease symptoms in pepper plants. Agrobacterium-mediated expression of XopAU in host and non-host plants activated typical defense responses, including MAP kinase phosphorylation, accumulation of pathogenesis-related (PR) proteins and elicitation of cell death, that were dependent on the kinase activity of the effector. XopAU-mediated cell death was not dependent on early signaling components of effector-triggered immunity and was also observed when the effector was delivered into pepper leaves by Xanthomonas campestris pv. campestris, but not by Xe. Protein-protein interaction studies in yeast and in planta revealed that XopAU physically interacts with components of plant immunity-associated MAP kinase cascades. Remarkably, XopAU directly phosphorylated MKK2 in vitro and enhanced its phosphorylation at multiple sites in planta. Consistent with the notion that MKK2 is a target of XopAU, silencing of the MKK2 homolog or overexpression of the catalytically inactive mutant MKK2K99R in N. benthamiana plants reduced XopAU-mediated cell death and MAPK phosphorylation. Furthermore, yeast co-expressing XopAU and MKK2 displayed reduced growth and this phenotype was dependent on the kinase activity of both proteins. Together, our results support the conclusion that XopAU contributes to Xe disease symptoms in pepper plants and manipulates host MAPK signaling through phosphorylation and activation of MKK2.
- Published
- 2018
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27. Utilization of diverse organophosphorus pollutants by marine bacteria
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Dragana Despotović, Einav Aharon, Olena Trofimyuk, Artem Dubovetskyi, Kesava Phaneendra Cherukuri, Yacov Ashani, Or Eliason, Martin Sperfeld, Haim Leader, Andrea Castelli, Laura Fumagalli, Alon Savidor, Yishai Levin, Liam M. Longo, Einat Segev, and Dan S. Tawfik
- Subjects
Aquatic Organisms ,Multidisciplinary ,Bacteria ,anthropogenic organophosphorus compounds ,bioremediation ,marine bacteria ,phosphotriesterases ,Biodegradation, Environmental ,Escherichia coli ,Indian Ocean ,Mediterranean Sea ,Phosphorus ,Seawater ,Environmental Pollutants ,Organophosphorus Compounds ,Phosphoric Triester Hydrolases ,Settore CHIM/08 - Chimica Farmaceutica ,Environmental ,Biodegradation - Abstract
Anthropogenic organophosphorus compounds (AOPCs), such as phosphotriesters, are used extensively as plasticizers, flame retardants, nerve agents, and pesticides. To date, only a handful of soil bacteria bearing a phosphotriesterase (PTE), the key enzyme in the AOPC degradation pathway, have been identified. Therefore, the extent to which bacteria are capable of utilizing AOPCs as a phosphorus source, and how widespread this adaptation may be, remains unclear. Marine environments with phosphorus limitation and increasing levels of pollution by AOPCs may drive the emergence of PTE activity. Here, we report the utilization of diverse AOPCs by four model marine bacteria and 17 bacterial isolates from the Mediterranean Sea and the Red Sea. To unravel the details of AOPC utilization, two PTEs from marine bacteria were isolated and characterized, with one of the enzymes belonging to a protein family that, to our knowledge, has never before been associated with PTE activity. When expressed in Escherichia coli with a phosphodiesterase, a PTE isolated from a marine bacterium enabled growth on a pesticide analog as the sole phosphorus source. Utilization of AOPCs may provide bacteria a source of phosphorus in depleted environments and offers a prospect for the bioremediation of a pervasive class of anthropogenic pollutants.
- Published
- 2022
28. DAP5 drives translation of specific mRNA targets with upstream ORFs in human embryonic stem cells
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David, Maya, primary, Olender, Tsviya, additional, Mizrahi, Orel, additional, Weingarten-Gabbay, Shira, additional, Friedlander, Gilgi, additional, Meril, Sara, additional, Goldberg, Nadav, additional, Savidor, Alon, additional, Levin, Yishai, additional, Salomon, Vered, additional, Stern-Ginossar, Noam, additional, Bialik, Shani, additional, and Kimchi, Adi, additional
- Published
- 2022
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29. Utilization of diverse organophosphorus pollutants by marine bacteria
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Despotović, Dragana, primary, Aharon, Einav, additional, Trofimyuk, Olena, additional, Dubovetskyi, Artem, additional, Cherukuri, Kesava Phaneendra, additional, Ashani, Yacov, additional, Eliason, Or, additional, Sperfeld, Martin, additional, Leader, Haim, additional, Castelli, Andrea, additional, Fumagalli, Laura, additional, Savidor, Alon, additional, Levin, Yishai, additional, Longo, Liam M., additional, Segev, Einat, additional, and Tawfik, Dan S., additional
- Published
- 2022
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30. Clavibacter michiganensis subsp. michiganensis Vatr1 and Vatr2 Transcriptional Regulators Are Required for Virulence in Tomato
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Alon Savidor, Laura Chalupowicz, Doron Teper, Karl-Heinz Gartemann, Rudolf Eichenlaub, Shulamit Manulis-Sasson, Isaac Barash, and Guido Sessa
- Subjects
Microbiology ,QR1-502 ,Botany ,QK1-989 - Abstract
The plant pathogen Clavibacter michiganensis subsp. michiganensis is a gram-positive bacterium responsible for wilt and canker disease of tomato. Although disease development is well characterized and diagnosed, molecular mechanisms of C. michiganensis subsp. michiganensis virulence are poorly understood. Here, we identified and characterized two C. michiganensis subsp. michiganensis transcriptional regulators, Vatr1 and Vatr2, that are involved in pathogenicity of C. michiganensis subsp. michiganensis. Vatr1 and Vatr2 belong to TetR and MocR families of transcriptional regulators, respectively. Mutations in their corresponding genes caused attenuated virulence, with the Δvatr2 mutant showing a more dramatic effect than Δvatr1. Although both mutants grew well in vitro and reached a high titer in planta, they caused reduced wilting and canker development in infected plants compared with the wild-type bacterium. They also led to a reduced expression of the ethylene-synthesizing tomato enzyme ACC-oxidase compared with wild-type C. michiganensis subsp. michiganensis and to reduced ethylene production in the plant. Transcriptomic analysis of wild-type C. michiganensis subsp. michiganensis and the two mutants under infection-mimicking conditions revealed that Vatr1 and Vatr2 regulate expression of virulence factors, membrane and secreted proteins, and signal-transducing proteins. A 70% overlap between the sets of genes positively regulated by Vatr1 and Vatr2 suggests that these transcriptional regulators are on the same molecular pathway responsible for C. michiganensis subsp. michiganensis virulence.
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- 2014
- Full Text
- View/download PDF
31. Identification and characterization of the key enzyme in the biosynthesis of the neurotoxin β-ODAP in grass pea
- Author
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Goldsmith, Moshe, primary, Barad, Shiri, additional, Knafo, Maor, additional, Savidor, Alon, additional, Ben-Dor, Shifra, additional, Brandis, Alexander, additional, Mehlman, Tevie, additional, Peleg, Yoav, additional, Albeck, Shira, additional, Dym, Orly, additional, Ben-Zeev, Efrat, additional, Barbole, Ranjit S., additional, Aharoni, Asaph, additional, and Reich, Ziv, additional
- Published
- 2022
- Full Text
- View/download PDF
32. DAP5 drives translation of specific mRNA targets with upstream ORFs in human embryonic stem cells
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Maya David, Tsviya Olender, Orel Mizrahi, Shira Weingarten-Gabbay, Gilgi Friedlander, Sara Meril, Nadav Goldberg, Alon Savidor, Yishai Levin, Vered Salomon, Noam Stern-Ginossar, Shani Bialik, and Adi Kimchi
- Subjects
Open Reading Frames ,Protein Biosynthesis ,Human Embryonic Stem Cells ,Histone Methyltransferases ,Humans ,Proteins ,RNA, Messenger ,Eukaryotic Initiation Factor-4G ,Molecular Biology - Abstract
Death associated protein 5 (DAP5/eIF4G2/NAT1) is a member of the eIF4G translation initiation factors that has been shown to mediate noncanonical and/or cap-independent translation. It is essential for embryonic development and for differentiation of embryonic stem cells (ESCs), specifically its ability to drive translation of specific target mRNAs. In order to expand the repertoire of DAP5 target mRNAs, we compared ribosome profiles in control and DAP5 knockdown (KD) human ESCs (hESCs) to identify mRNAs with decreased ribosomal occupancy upon DAP5 silencing. A cohort of 68 genes showed decreased translation efficiency in DAP5 KD cells. Mass spectrometry confirmed decreased protein abundance of a significant portion of these targets. Among these was KMT2D, a histone methylase previously shown to be essential for ESC differentiation and embryonic development. We found that nearly half of the cohort of DAP5 target mRNAs displaying reduced translation efficiency of their main coding sequences upon DAP5 KD contained upstream open reading frames (uORFs) that are actively translated independently of DAP5. This is consistent with previously suggested mechanisms by which DAP5 mediates leaky scanning through uORFs and/or reinitiation at the main coding sequence. Crosslinking protein–RNA immunoprecipitation experiments indicated that a significant subset of DAP5 mRNA targets bound DAP5, indicating that direct binding between DAP5 protein and its target mRNAs is a frequent but not absolute requirement for DAP5-dependent translation of the main coding sequence. Thus, we have extended DAP5's function in translation of specific mRNAs in hESCs by a mechanism allowing translation of the main coding sequence following upstream translation of short ORFs.
- Published
- 2022
33. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischaemic injury
- Author
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Avraham Shakked, Zachary Petrover, Alla Aharonov, Matteo Ghiringhelli, Kfir-Baruch Umansky, Phong Dang Nguyen, David Kain, Jacob Elkahal, Yalin Divinsky, Shoval Miyara, Gilgi Friedlander, Alon Savidor, Lingling Zhang, Dahlia Perez, Nathaniel Kastan, Daria Lendengolts, Yishai Levin, Jeroen Bakkers, Lior Gepstein, and Eldad Tzahor
- Abstract
Cardiomyocyte renewal by dedifferentiation and proliferation has fueled the field of regenerative cardiology in recent years, while the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterised by the restoration of function that is lost during dedifferentiation and is key to the healing process following injury. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: dedifferentiation, followed by redifferentiation. Here, using temporal RNAseq and proteomics, we survey the landscape of the dedifferentiation-redifferentiation process in the adult mouse heart. We find well characterised dedifferentiation pathways, such as reduced oxphos, increased proliferation and increased EMT-like features, largely return to normal, though elements of residual dedifferentiation remain, even after contractile function is restored. These hearts appeared rejuvenated and showed robust resistance to ischaemic injury. We find that redifferentiation is driven by negative feedback signalling, notably through LATS1/2 Hippo pathway activity. Disabling LATS1/2 in dedifferentiated cardiomyocytes augments dedifferentiation in vitro and prevents redifferentiation in vivo. Taken together, our data reveal the non-trivial nature of redifferentiation, whereby elements of dedifferentiation linger in a surprisingly beneficial manner. This cycle of dedifferentiation-redifferentiation protects against future insult, in what could become a novel prophylactic treatment against ischemic heart disease for at-risk patients.
- Published
- 2022
34. Communication between viruses guides lysis–lysogeny decisions
- Author
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Erez, Zohar, Steinberger-Levy, Ida, Shamir, Maya, Doron, Shany, Stokar-Avihail, Avigail, Peleg, Yoav, Melamed, Sarah, Leavitt, Azita, Savidor, Alon, Albeck, Shira, Amitai, Gil, and Sorek, Rotem
- Published
- 2017
- Full Text
- View/download PDF
35. Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischaemic injury
- Author
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Shakked, Avraham, primary, Petrover, Zachary, additional, Aharonov, Alla, additional, Ghiringhelli, Matteo, additional, Umansky, Kfir-Baruch, additional, Nguyen, Phong Dang, additional, Kain, David, additional, Elkahal, Jacob, additional, Divinsky, Yalin, additional, Miyara, Shoval, additional, Friedlander, Gilgi, additional, Savidor, Alon, additional, Zhang, Lingling, additional, Perez, Dahlia, additional, Kastan, Nathaniel, additional, Lendengolts, Daria, additional, Levin, Yishai, additional, Bakkers, Jeroen, additional, Gepstein, Lior, additional, and Tzahor, Eldad, additional
- Published
- 2022
- Full Text
- View/download PDF
36. A new function for the serine protease HtrA2 in controlling radiation‐induced senescence in cancer cells
- Author
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Hammer, Liat, primary, Levin‐Salomon, Vered, additional, Yaeli‐Slonim, Naama, additional, Weiss, Moria, additional, Dekel‐Bird, Naama P., additional, Olender, Tsviya, additional, Porat, Ziv, additional, Winograd‐Katz, Sabina, additional, Savidor, Alon, additional, Levin, Yishai, additional, Bialik, Shani, additional, Geiger, Benjamin, additional, and Kimchi, Adi, additional
- Published
- 2022
- Full Text
- View/download PDF
37. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration
- Author
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Daria Lendengolts, Or-Yam Revach, Alon Savidor, Alla Aharonov, James F. Martin, Eldad Tzahor, Benjamin Geiger, Kfir Baruch Umansky, Alexander Genzelinakh, Yuka Morikawa, Avraham Shakked, Jixin Dong, Yishai Levin, and David Kain
- Subjects
MAPK/ERK pathway ,Epithelial-Mesenchymal Transition ,Receptor, ErbB-2 ,Myocardial Infarction ,Cell Cycle Proteins ,Mice, Transgenic ,Mechanotransduction, Cellular ,03 medical and health sciences ,0302 clinical medicine ,Mediator ,Animals ,Regeneration ,Myocyte ,Myocytes, Cardiac ,Epithelial–mesenchymal transition ,Phosphorylation ,Mechanotransduction ,Extracellular Signal-Regulated MAP Kinases ,Cytoskeleton ,Cells, Cultured ,health care economics and organizations ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,030304 developmental biology ,Heart Failure ,0303 health sciences ,Cell growth ,Chemistry ,YAP-Signaling Proteins ,Cell Biology ,Fibrosis ,Cell biology ,Disease Models, Animal ,Crosstalk (biology) ,030220 oncology & carcinogenesis - Abstract
Cardiomyocyte loss after injury results in adverse remodelling and fibrosis, inevitably leading to heart failure. The ERBB2-Neuregulin and Hippo-YAP signalling pathways are key mediators of heart regeneration, yet the crosstalk between them is unclear. We demonstrate that transient overexpression of activated ERBB2 in cardiomyocytes (OE CMs) promotes cardiac regeneration in a heart failure model. OE CMs present an epithelial-mesenchymal transition (EMT)-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration and extracellular matrix turnover. We identified YAP as a critical mediator of ERBB2 signalling. In OE CMs, YAP interacts with nuclear-envelope and cytoskeletal components, reflecting an altered mechanical state elicited by ERBB2. We identified two YAP-activating phosphorylations on S352 and S274 in OE CMs, which peak during metaphase, that are ERK dependent and Hippo independent. Viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Together, we reveal a potent ERBB2-mediated YAP mechanotransduction signalling, involving EMT-like characteristics, resulting in robust heart regeneration.
- Published
- 2020
38. Genome Sequencing and Mapping Reveal Loss of Heterozygosity as a Mechanism for Rapid Adaptation in the Vegetable Pathogen Phytophthora capsici
- Author
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Kurt H. Lamour, Joann Mudge, Daniel Gobena, Oscar P. Hurtado-Gonzales, Jeremy Schmutz, Alan Kuo, Neil A. Miller, Brandon J. Rice, Sylvain Raffaele, Liliana M. Cano, Arvind K. Bharti, Ryan S. Donahoo, Sabra Finley, Edgar Huitema, Jon Hulvey, Darren Platt, Asaf Salamov, Alon Savidor, Rahul Sharma, Remco Stam, Dylan Storey, Marco Thines, Joe Win, Brian J. Haas, Darrell L. Dinwiddie, Jerry Jenkins, James R. Knight, Jason P. Affourtit, Cliff S. Han, Olga Chertkov, Erika A. Lindquist, Chris Detter, Igor V. Grigoriev, Sophien Kamoun, and Stephen F. Kingsmore
- Subjects
Microbiology ,QR1-502 ,Botany ,QK1-989 - Abstract
The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.
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- 2012
- Full Text
- View/download PDF
39. Identification and characterization of the key enzyme in the biosynthesis of the neurotoxin β-ODAP in grass pea
- Author
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Moshe Goldsmith, Shiri Barad, Maor Knafo, Alon Savidor, Shifra Ben-Dor, Alexander Brandis, Tevie Mehlman, Yoav Peleg, Shira Albeck, Orly Dym, Efrat Ben-Zeev, Ranjit S. Barbole, Asaph Aharoni, and Ziv Reich
- Subjects
Molecular Docking Simulation ,Lathyrus ,Acetyltransferases ,Neurotoxins ,Amino Acids, Diamino ,Cell Biology ,Molecular Biology ,Biochemistry - Abstract
Grass pea (Lathyrus sativus L.) is a grain legume commonly grown in Asia and Africa for food and forage. It is a highly nutritious and robust crop, capable of surviving both droughts and floods. However, it produces a neurotoxic compound, β-N-oxalyl-L-α,β-diaminopropionic acid (β-ODAP), which can cause a severe neurological disorder when consumed as a primary diet component. While the catalytic activity associated with β-ODAP formation was demonstrated more than 50 years ago, the enzyme responsible for this activity has not been identified. Here, we report on the identity, activity, 3D structure, and phylogenesis of this enzyme-β-ODAP synthase (BOS). We show that BOS belongs to the benzylalcohol O-acetyltransferase, anthocyanin O-hydroxycinnamoyltransferase, anthranilate N-hydroxycinnamoyl/benzoyltransferase, deacetylvindoline 4-O-acetyltransferase superfamily of acyltransferases and is structurally similar to hydroxycinnamoyl transferase. Using molecular docking, we propose a mechanism for its catalytic activity, and using heterologous expression in tobacco leaves (Nicotiana benthamiana), we demonstrate that expression of BOS in the presence of its substrates is sufficient for β-ODAP production in vivo. The identification of BOS may pave the way toward engineering β-ODAP-free grass pea cultivars, which are safe for human and animal consumption.
- Published
- 2021
40. Host transcriptome signatures in human faecal-washes predict histological remission in patients with IBD
- Author
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Ungar, Bella, primary, Yavzori, Miri, additional, Fudim, Ella, additional, Picard, Orit, additional, Kopylov, Uri, additional, Eliakim, Rami, additional, Shouval, Dror, additional, Levin, Yishai, additional, Savidor, Alon, additional, Ben-Moshe, Shani, additional, Manco, Rita, additional, Dan, Stav, additional, Egozi, Adi, additional, Bahar Halpern, Keren, additional, Mayer, Chen, additional, Barshack, Iris, additional, Ben-Horin, Shomron, additional, and Itzkovitz, Shalev, additional
- Published
- 2022
- Full Text
- View/download PDF
41. P032 Host transcriptome signatures in human fecal-washes predict histological remission in IBD patients
- Author
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Ungar, B, primary, Yavzori, M, additional, Fudim, E, additional, Picard, O, additional, Kopylov, U, additional, Eliakim, R, additional, Shouval, D, additional, Levin, Y, additional, Savidor, A, additional, Ben-Moshe, S, additional, Manco, R, additional, Dan, S, additional, Egozi, A, additional, Bahar Halpern, K, additional, Mayer, C, additional, Barshak, I, additional, Ben-Horin, S, additional, and Itzkovitz, S, additional
- Published
- 2022
- Full Text
- View/download PDF
42. SPEAR: A proteomics approach for simultaneous protein expression and redox analysis
- Author
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Doron, Shani, primary, Lampl, Nardy, additional, Savidor, Alon, additional, Katina, Corine, additional, Gabashvili, Alexandra, additional, Levin, Yishai, additional, and Rosenwasser, Shilo, additional
- Published
- 2021
- Full Text
- View/download PDF
43. Widespread Utilization of Diverse Organophosphate Pollutants by Marine Bacteria
- Author
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Alon Savidor, Olena Trofimyuk, Andrea Castelli, Dan S. Tawfik, Yishai Levin, Artem Dubovetskyi, Liam M. Longo, Yacov Ashani, Dragana Despotovic, Einat Segev, Einav Aharon, Laura Fumagalli, Haim Leader, and Kesava Phaneendra Cherukuri
- Subjects
Pollutant ,biology ,Phosphorus ,Organophosphate ,chemistry.chemical_element ,Pesticide ,biology.organism_classification ,chemistry.chemical_compound ,Marine bacteriophage ,Bioremediation ,chemistry ,Environmental chemistry ,Environmental science ,Anthropogenic pollutants ,Bacteria - Abstract
Anthropogenic organophosphates (AOPs), such as phosphotriesters, are used extensively as plasticizers, flame retardants, nerve agents and pesticides. Soil bacteria bearing a phosphotriesterase (PTE) can degrade AOPs, but whether bacteria are capable of utilizing AOPs as a phosphorus source, and how widespread PTEs are in nature, remains unclear. Here, we report the utilization of diverse AOPs by four model marine bacteria and seventeen bacterial isolates from seawater samples. To unravel the details of AOP utilization, two novel PTEs from marine bacteria were isolated and characterized. When expressed in E. coli, these PTEs enabled growth on a pesticide analog as the sole phosphorus source. Utilization of AOPs provides bacteria with a source of phosphorus in depleted environments and offers a new prospect for the bioremediation of a pervasive class of anthropogenic pollutants.One sentence summaryWidespread utilization of diverse organophosphate pollutants by over 20 marine bacterial strains represents a new hope for ocean bioremediation.
- Published
- 2021
44. Identification of a biomarker in cerebrospinal fluid for neuronopathic forms of Gaucher disease.
- Author
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Hila Zigdon, Alon Savidor, Yishai Levin, Anna Meshcheriakova, Raphael Schiffmann, and Anthony H Futerman
- Subjects
Medicine ,Science - Abstract
Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.
- Published
- 2015
- Full Text
- View/download PDF
45. Disturbance of the bacterial cell wall specifically interferes with biofilm formation
- Author
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Bucher, Tabitha, Oppenheimer-Shaanan, Yaara, Savidor, Alon, Bloom-Ackermann, Zohar, and Kolodkin-Gal, Ilana
- Published
- 2015
- Full Text
- View/download PDF
46. Host transcriptome signatures in human faecal-washes predict histological remission in patients with IBD
- Author
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Bella Ungar, Miri Yavzori, Ella Fudim, Orit Picard, Uri Kopylov, Rami Eliakim, Dror Shouval, Yishai Levin, Alon Savidor, Shani Ben-Moshe, Rita Manco, Stav Dan, Adi Egozi, Keren Bahar Halpern, Chen Mayer, Iris Barshack, Shomron Ben-Horin, and Shalev Itzkovitz
- Subjects
Gastroenterology - Abstract
BackgroundColonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features.AimsTo assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls.MethodsIn this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes.ResultsWe analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10−12). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve >0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells.ConclusionsFaecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.
- Published
- 2021
47. SPEAR: a proteomics approach for simultaneous protein expression and redox analysis
- Author
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Alon Savidor, Nardy Lampl, Shilo Rosenwasser, Alexandra Gabashvili, Shani Doron, Corine Katina, and Yishai Levin
- Subjects
Proteomics ,Proteome ,biology ,Oxidative phosphorylation ,Subcellular localization ,biology.organism_classification ,Biochemistry ,Redox ,Protein structure ,Physiology (medical) ,Arabidopsis ,Biophysics ,Cysteine ,Oxidation-Reduction ,Protein Processing, Post-Translational - Abstract
Oxidation and reduction of protein cysteinyl thiols serve as molecular switches, which is considered the most central mechanism for redox regulation of biological processes, altering protein structure, biochemical activity, subcellular localization, and binding affinity. Redox proteomics allows for the global identification of redox-modified cysteine (Cys) sites and quantification of their oxidation/reduction responses, serving as a hypothesis-generating platform to stimulate redox biology mechanistic research. Here, we developed Simultaneous Protein Expression and Redox (SPEAR) analysis, a new redox-proteomics approach based on differential labeling of oxidized and reduced cysteines with light and heavy isotopic forms of commercially available isotopically-labeled N-ethylmaleimide (NEM). The presented method does not require enrichment for labeled peptides, thus enabling simultaneous quantification of Cys oxidation state and protein abundance. Using SPEAR, we were able to quantify the in-vivo oxidation state of thousands of cysteines across the Arabidopsis proteome under steady-state and oxidative stress conditions. Functional assignment of the identified redox-sensitive proteins demonstrated the widespread effect of oxidative conditions on various cellular functions and highlighted the enrichment of chloroplast-targeted proteins. SPEAR provides a simple, straightforward, and cost-effective means of studying redox proteome dynamics. The presented data provide a global quantitative view of cysteine oxidation of well-known redox-regulated active sites and many novel redox-sensitive sites whose role in plant acclimation to stress conditions remains to be further explored.
- Published
- 2021
48. Widespread Utilization of Diverse Organophosphate Pollutants by Marine Bacteria
- Author
-
Despotovic, Dragana, primary, Aharon, Einav, additional, Trofimyuk, Olena, additional, Dubovetskyi, Artem, additional, Cherukuri, Kesava Phaneendra, additional, Ashani, Yacov, additional, Leader, Haim, additional, Castelli, Andrea, additional, Fumagalli, Laura, additional, Savidor, Alon, additional, Levin, Yishai, additional, Longo, Liam M, additional, Segev, Einat, additional, and Tawfik, Dan S, additional
- Published
- 2021
- Full Text
- View/download PDF
49. P032 Host transcriptome signatures in human fecal-washes predict histological remission in IBD patients
- Author
-
B Ungar, M Yavzori, E Fudim, O Picard, U Kopylov, R Eliakim, D Shouval, Y Levin, A Savidor, S Ben-Moshe, R Manco, S Dan, A Egozi, K Bahar Halpern, C Mayer, I Barshak, S Ben-Horin, and S Itzkovitz
- Subjects
Gastroenterology ,General Medicine - Abstract
Background Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBD), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features. Our aim was to assess the utility of host transcriptomics of fecal wash samples of IBD patients compared to controls. Methods In this prospective cohort study, we obtained biopsies and fecal-wash samples from IBD patients and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching fecal-washes, and associated them with endoscopic and histological inflammation status. We also performed fecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes. Results We analyzed biopsies and fecal washes from 39 patients (19 IBD, 20 controls). Host fecal-transcriptome carried information that was distinct from biopsy RNAseq and fecal proteomics. Transcriptomics of fecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3*10–12). Fecal-transcriptome was significantly more powerful in identifying histological inflammation compared to transcriptome of intestinal biopsies (150 genes with area-under-the-curve >0.9 in fecal samples versus 10 genes in biopsy RNAseq). Fecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells. Figure 1 - Fecal-wash host transcriptome predicts histological inflammation. A) Study layout, B) Clustergram of fecal-wash host cell mRNA signatures, demonstrating that patients with histological inflammation (red) are clustered when measuring fecal wash transcriptome yet not biopsy transcriptomes. C-D) Principle Component Analysis demonstrating improved separation of inflamed patients based on fecal host transcriptomes. E, F) Expression of host genes in fecal washes has higher statistical power (Area under the Curve, AUC) in classifying histological inflammation compared to biopsies. D shows NFKBIA as an example, E shows the AUC of the 5% best classifying genes, F shows the overall AUC based on biopsies or washes. Gray areas have AUC>0.9. G) UMAP of cells obtained from scRNAseq of mouse small intestine fecal washes. Conclusion Fecal wash host transcriptome is a powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscure using biopsy transctriptomics.
- Published
- 2022
50. The Serine Protease HtrA2 mediates radiation-induced senescence in cancer cells
- Author
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Tsviya Olender, Yishai Levin, Alon Savidor, Benjamin Geiger, Liat Hammer, Shani Bialik, Vered Levin-Salomon, Moria Weiss, Sabina Winograd-Katz, Ziv Porat, Adi Kimchi, Naama Yaeli-Slonim, and Naama Pnina Dekel-Bird
- Subjects
Senescence ,biology ,Cytoskeleton organization ,DNA repair ,Cell growth ,Chemistry ,Cell ,Vimentin ,Cell biology ,medicine.anatomical_structure ,Downregulation and upregulation ,Cancer cell ,medicine ,biology.protein - Abstract
Radiation therapy can induce cellular senescence in cancer cells leading to short-term tumor growth arrest, yet increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells, which exhibited a typical senescent phenotype, including upregulation of p53 and its target p21, followed by sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence-associated beta-galactosidase activity. A functional siRNA screen using a cell death-related library identified the mitochondrial Ser protease HtrA2 as necessary for senescence development. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy, while irradiation with HtrA2 inhibition upregulated cell proliferation components. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus HtrA2, contributes to several hallmarks of senescence and is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence.SummaryHere the authors identify the Ser protease HtrA2 as a novel mediator of radiation-induced senescence, necessary for sustained proliferation arrest and reorganization of the vimentin filament network.
- Published
- 2021
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