المؤلفون: Jang, Gwendolyn M, Sudarsan, Arun Kumar Annan, Shayeganmehr, Arzhang, Munhoz, Erika Prando, Lao, Reanna, Gaba, Amit, Rodríguez, Milaid Granadillo, Love, Robin P, Polacco, Benjamin J, Zhou, Yuan, Krogan, Nevan J, Kaake, Robyn M, Chelico, Linda

المصدر: Molecular & Cellular Proteomics. 23(5)

مصطلحات موضوعية: Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Genetics, Cancer, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Generic health relevance, APOBEC3, DNA, RNA, cMyc, cancer, deaminase, protein-protein interactions, restriction factor, Biochemistry & Molecular Biology

الوصف: Human APOBEC3 enzymes are a family of single-stranded (ss)DNA and RNA cytidine deaminases that act as part of the intrinsic immunity against viruses and retroelements. These enzymes deaminate cytosine to form uracil which can functionally inactivate or cause degradation of viral or retroelement genomes. In addition, APOBEC3s have deamination-independent antiviral activity through protein and nucleic acid interactions. If expression levels are misregulated, some APOBEC3 enzymes can access the human genome leading to deamination and mutagenesis, contributing to cancer initiation and evolution. While APOBEC3 enzymes are known to interact with large ribonucleoprotein complexes, the function and RNA dependence are not entirely understood. To further understand their cellular roles, we determined by affinity purification mass spectrometry (AP-MS) the protein interaction network for the human APOBEC3 enzymes and mapped a diverse set of protein-protein and protein-RNA mediated interactions. Our analysis identified novel RNA-mediated interactions between APOBEC3C, APOBEC3H Haplotype I and II, and APOBEC3G with spliceosome proteins, and APOBEC3G and APOBEC3H Haplotype I with proteins involved in tRNA methylation and ncRNA export from the nucleus. In addition, we identified RNA-independent protein-protein interactions with APOBEC3B, APOBEC3D, and APOBEC3F and the prefoldin family of protein-folding chaperones. Interaction between prefoldin 5 (PFD5) and APOBEC3B disrupted the ability of PFD5 to induce degradation of the oncogene cMyc, implicating the APOBEC3B protein interaction network in cancer. Altogether, the results uncover novel functions and interactions of the APOBEC3 family and suggest they may have fundamental roles in cellular RNA biology, their protein-protein interactions are not redundant, and there are protein-protein interactions with tumor suppressors, suggesting a role in cancer biology. Data are available via ProteomeXchange with the identifier PXD044275.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3tk6h06jTest

المؤلفون: Cakir, Zeynep, Lord, Samuel J, Zhou, Yuan, Jang, Gwendolyn M, Polacco, Benjamin J, Eckhardt, Manon, Jimenez-Morales, David, Newton, Billy W, Orr, Adam L, Johnson, Jeffrey R, da Cruz, Alexandre, Mullins, R Dyche, Krogan, Nevan J, Mahley, Robert W, Swaney, Danielle L

المصدر: Molecular & Cellular Proteomics. 22(5)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Acquired Cognitive Impairment, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Brain Disorders, Dementia, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Actins, Alzheimer Disease, Apolipoprotein E3, Apolipoprotein E4, Apolipoproteins E, Phosphorylation, Proteomics, Animals, Mice, Alzheimer’s disease, Kinase, Protein-protein interaction, Ubiquitylation, Biochemistry & Molecular Biology

الوصف: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here, we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in vasodilator-stimulated phosphoprotein (VASP) S235 phosphorylation in a protein kinase A (PKA)-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9sc0x4p1Test

المؤلفون: Haas, Kelsey M, McGregor, Michael J, Bouhaddou, Mehdi, Polacco, Benjamin J, Kim, Eun-Young, Nguyen, Thong T, Newton, Billy W, Urbanowski, Matthew, Kim, Heejin, Williams, Michael AP, Rezelj, Veronica V, Hardy, Alexandra, Fossati, Andrea, Stevenson, Erica J, Sukerman, Ellie, Kim, Tiffany, Penugonda, Sudhir, Moreno, Elena, Braberg, Hannes, Zhou, Yuan, Metreveli, Giorgi, Harjai, Bhavya, Tummino, Tia A, Melnyk, James E, Soucheray, Margaret, Batra, Jyoti, Pache, Lars, Martin-Sancho, Laura, Carlson-Stevermer, Jared, Jureka, Alexander S, Basler, Christopher F, Shokat, Kevan M, Shoichet, Brian K, Shriver, Leah P, Johnson, Jeffrey R, Shaw, Megan L, Chanda, Sumit K, Roden, Dan M, Carter, Tonia C, Kottyan, Leah C, Chisholm, Rex L, Pacheco, Jennifer A, Smith, Maureen E, Schrodi, Steven J, Albrecht, Randy A, Vignuzzi, Marco, Zuliani-Alvarez, Lorena, Swaney, Danielle L, Eckhardt, Manon, Wolinsky, Steven M, White, Kris M, Hultquist, Judd F, Kaake, Robyn M, García-Sastre, Adolfo, Krogan, Nevan J

المصدر: Nature Communications. 14(1)

مصطلحات موضوعية: Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Infectious Diseases, Prevention, Emerging Infectious Diseases, Vaccine Related, Influenza, Pneumonia & Influenza, Biodefense, Biotechnology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, Infection, Humans, Influenza A virus, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H3N2 Subtype, Proteomics, Virus Replication, COVID-19, SARS-CoV-2, Antiviral Agents, Host-Pathogen Interactions

الوصف: Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5h41d3svTest

المؤلفون: Hota, Swetansu K, Rao, Kavitha S, Blair, Andrew P, Khalilimeybodi, Ali, Hu, Kevin M, Thomas, Reuben, So, Kevin, Kameswaran, Vasumathi, Xu, Jiewei, Polacco, Benjamin J, Desai, Ravi V, Chatterjee, Nilanjana, Hsu, Austin, Muncie, Jonathon M, Blotnick, Aaron M, Winchester, Sarah AB, Weinberger, Leor S, Hüttenhain, Ruth, Kathiriya, Irfan S, Krogan, Nevan J, Saucerman, Jeffrey J, Bruneau, Benoit G

المصدر: Nature. 602(7895)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Animals, Bone Morphogenetic Protein 4, Cell Differentiation, Cell Lineage, Chromatin, Chromatin Assembly and Disassembly, DNA Helicases, Embryo, Mammalian, Epigenesis, Genetic, Female, Gene Expression Regulation, Male, Mesoderm, Mice, Myocardium, Myocytes, Cardiac, Neurogenesis, Neurons, Nuclear Proteins, Octamer Transcription Factor-6, Phenotype, Repressor Proteins, Stem Cells, Time Factors, Transcription Factors, General Science & Technology

الوصف: Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0s20m15cTest

المؤلفون: Bouhaddou, Mehdi, Memon, Danish, Meyer, Bjoern, White, Kris M, Rezelj, Veronica V, Correa Marrero, Miguel, Polacco, Benjamin J, Melnyk, James E, Ulferts, Svenja, Kaake, Robyn M, Batra, Jyoti, Richards, Alicia L, Stevenson, Erica, Gordon, David E, Rojc, Ajda, Obernier, Kirsten, Fabius, Jacqueline M, Soucheray, Margaret, Miorin, Lisa, Moreno, Elena, Koh, Cassandra, Tran, Quang Dinh, Hardy, Alexandra, Robinot, Rémy, Vallet, Thomas, Nilsson-Payant, Benjamin E, Hernandez-Armenta, Claudia, Dunham, Alistair, Weigang, Sebastian, Knerr, Julian, Modak, Maya, Quintero, Diego, Zhou, Yuan, Dugourd, Aurelien, Valdeolivas, Alberto, Patil, Trupti, Li, Qiongyu, Hüttenhain, Ruth, Cakir, Merve, Muralidharan, Monita, Kim, Minkyu, Jang, Gwendolyn, Tutuncuoglu, Beril, Hiatt, Joseph, Guo, Jeffrey Z, Xu, Jiewei, Bouhaddou, Sophia, Mathy, Christopher JP, Gaulton, Anna, Manners, Emma J, Félix, Eloy, Shi, Ying, Goff, Marisa, Lim, Jean K, McBride, Timothy, O'Neal, Michael C, Cai, Yiming, Chang, Jason CJ, Broadhurst, David J, Klippsten, Saker, De Wit, Emmie, Leach, Andrew R, Kortemme, Tanja, Shoichet, Brian, Ott, Melanie, Saez-Rodriguez, Julio, tenOever, Benjamin R, Mullins, R Dyche, Fischer, Elizabeth R, Kochs, Georg, Grosse, Robert, García-Sastre, Adolfo, Vignuzzi, Marco, Johnson, Jeffery R, Shokat, Kevan M, Swaney, Danielle L, Beltrao, Pedro, Krogan, Nevan J

المصدر: Cell. 182(3)

مصطلحات موضوعية: Caco-2 Cells, Vero Cells, Animals, Humans, Pneumonia, Viral, Coronavirus Infections, Peptidyl-Dipeptidase A, Casein Kinase II, Cyclin-Dependent Kinases, p38 Mitogen-Activated Protein Kinases, Receptor Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Protein Kinase Inhibitors, Antiviral Agents, Drug Evaluation, Preclinical, Proteomics, Phosphorylation, Host-Pathogen Interactions, Phosphatidylinositol 3-Kinases, HEK293 Cells, Pandemics, Spike Glycoprotein, Coronavirus, A549 Cells, Betacoronavirus, Phosphoinositide-3 Kinase Inhibitors, Chlorocebus aethiops, COVID-19, Angiotensin-Converting Enzyme 2, SARS-CoV-2, AXL, CDK, MAPK, PIKFYVE, antiviral, casein kinase II, mass spectrometry, p38, phosphoproteomics, Infectious Diseases, Prevention, Biodefense, Emerging Infectious Diseases, Vaccine Related, Lung, Infection, Developmental Biology, Biological Sciences, Medical and Health Sciences

الوصف: The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4431p9mqTest

المؤلفون: Gordon, David E, Jang, Gwendolyn M, Bouhaddou, Mehdi, Xu, Jiewei, Obernier, Kirsten, White, Kris M, O’Meara, Matthew J, Rezelj, Veronica V, Guo, Jeffrey Z, Swaney, Danielle L, Tummino, Tia A, Hüttenhain, Ruth, Kaake, Robyn M, Richards, Alicia L, Tutuncuoglu, Beril, Foussard, Helene, Batra, Jyoti, Haas, Kelsey, Modak, Maya, Kim, Minkyu, Haas, Paige, Polacco, Benjamin J, Braberg, Hannes, Fabius, Jacqueline M, Eckhardt, Manon, Soucheray, Margaret, Bennett, Melanie J, Cakir, Merve, McGregor, Michael J, Li, Qiongyu, Meyer, Bjoern, Roesch, Ferdinand, Vallet, Thomas, Mac Kain, Alice, Miorin, Lisa, Moreno, Elena, Naing, Zun Zar Chi, Zhou, Yuan, Peng, Shiming, Shi, Ying, Zhang, Ziyang, Shen, Wenqi, Kirby, Ilsa T, Melnyk, James E, Chorba, John S, Lou, Kevin, Dai, Shizhong A, Barrio-Hernandez, Inigo, Memon, Danish, Hernandez-Armenta, Claudia, Lyu, Jiankun, Mathy, Christopher JP, Perica, Tina, Pilla, Kala Bharath, Ganesan, Sai J, Saltzberg, Daniel J, Rakesh, Ramachandran, Liu, Xi, Rosenthal, Sara B, Calviello, Lorenzo, Venkataramanan, Srivats, Liboy-Lugo, Jose, Lin, Yizhu, Huang, Xi-Ping, Liu, YongFeng, Wankowicz, Stephanie A, Bohn, Markus, Safari, Maliheh, Ugur, Fatima S, Koh, Cassandra, Savar, Nastaran Sadat, Tran, Quang Dinh, Shengjuler, Djoshkun, Fletcher, Sabrina J, O’Neal, Michael C, Cai, Yiming, Chang, Jason CJ, Broadhurst, David J, Klippsten, Saker, Sharp, Phillip P, Wenzell, Nicole A, Kuzuoglu-Ozturk, Duygu, Wang, Hao-Yuan, Trenker, Raphael, Young, Janet M, Cavero, Devin A, Hiatt, Joseph, Roth, Theodore L, Rathore, Ujjwal, Subramanian, Advait, Noack, Julia, Hubert, Mathieu, Stroud, Robert M, Frankel, Alan D, Rosenberg, Oren S, Verba, Kliment A, Agard, David A, Ott, Melanie, Emerman, Michael, Jura, Natalia

المصدر: Nature. 583(7816)

مصطلحات موضوعية: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Coronaviruses, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses Therapeutics and Interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Animals, Antiviral Agents, Betacoronavirus, COVID-19, Chlorocebus aethiops, Cloning, Molecular, Coronavirus Infections, Drug Evaluation, Preclinical, Drug Repositioning, HEK293 Cells, Host-Pathogen Interactions, Humans, Immunity, Innate, Mass Spectrometry, Molecular Targeted Therapy, Pandemics, Pneumonia, Viral, Protein Binding, Protein Biosynthesis, Protein Domains, Protein Interaction Mapping, Protein Interaction Maps, Receptors, sigma, SARS-CoV-2, SKP Cullin F-Box Protein Ligases, Vero Cells, Viral Proteins, COVID-19 Drug Treatment, General Science & Technology

الوصف: A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2gt3q50xTest
https://escholarship.org/content/qt2gt3q50x/qt2gt3q50x.pdfTest

المؤلفون: Gordon, David E, Jang, Gwendolyn M, Bouhaddou, Mehdi, Xu, Jiewei, Obernier, Kirsten, O'Meara, Matthew J, Guo, Jeffrey Z, Swaney, Danielle L, Tummino, Tia A, Hüttenhain, Ruth, Kaake, Robyn M, Richards, Alicia L, Tutuncuoglu, Beril, Foussard, Helene, Batra, Jyoti, Haas, Kelsey, Modak, Maya, Kim, Minkyu, Haas, Paige, Polacco, Benjamin J, Braberg, Hannes, Fabius, Jacqueline M, Eckhardt, Manon, Soucheray, Margaret, Bennett, Melanie J, Cakir, Merve, McGregor, Michael J, Li, Qiongyu, Naing, Zun Zar Chi, Zhou, Yuan, Peng, Shiming, Kirby, Ilsa T, Melnyk, James E, Chorba, John S, Lou, Kevin, Dai, Shizhong A, Shen, Wenqi, Shi, Ying, Zhang, Ziyang, Barrio-Hernandez, Inigo, Memon, Danish, Hernandez-Armenta, Claudia, Mathy, Christopher JP, Perica, Tina, Pilla, Kala B, Ganesan, Sai J, Saltzberg, Daniel J, Ramachandran, Rakesh, Liu, Xi, Rosenthal, Sara B, Calviello, Lorenzo, Venkataramanan, Srivats, Lin, Yizhu, Wankowicz, Stephanie A, Bohn, Markus, Trenker, Raphael, Young, Janet M, Cavero, Devin, Hiatt, Joe, Roth, Theo, Rathore, Ujjwal, Subramanian, Advait, Noack, Julia, Hubert, Mathieu, Roesch, Ferdinand, Vallet, Thomas, Meyer, Björn, White, Kris M, Miorin, Lisa, Agard, David, Emerman, Michael, Ruggero, Davide, García-Sastre, Adolfo, Jura, Natalia, von Zastrow, Mark, Taunton, Jack, Schwartz, Olivier, Vignuzzi, Marco, d'Enfert, Christophe, Mukherjee, Shaeri, Jacobson, Matt, Malik, Harmit S, Fujimori, Danica G, Ideker, Trey, Craik, Charles S, Floor, Stephen, Fraser, James S, Gross, John, Sali, Andrej, Kortemme, Tanja, Beltrao, Pedro, Shokat, Kevan, Shoichet, Brian K, Krogan, Nevan J

مصطلحات موضوعية: Prevention, Vaccine Related, Biodefense, Infectious Diseases, Rare Diseases, Pneumonia & Influenza, Emerging Infectious Diseases, Lung, Pneumonia, 5.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, Infection

الوصف: An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity- purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9v71w6zcTest

المؤلفون: Kehrer, Thomas, Cupic, Anastasija, Ye, Chengjin, Yildiz, Soner, Bouhaddou, Mehdi, Crossland, Nicholas A, Barrall, Erika A, Cohen, Phillip, Tseng, Anna, Çağatay, Tolga, Rathnasinghe, Raveen, Flores, Daniel, Jangra, Sonia, Alam, Fahmida, Mena, Ignacio, Aslam, Sadaf, Saqi, Anjali, Rutkowska, Magdalena, Ummadi, Manisha R, Pisanelli, Giuseppe, Richardson, R Blake, Veit, Ethan C, Fabius, Jacqueline M, Soucheray, Margaret, Polacco, Benjamin J, Ak, Baran, Marin, Arturo, Evans, Matthew J, Swaney, Danielle L, Gonzalez-Reiche, Ana S, Sordillo, Emilia M, van Bakel, Harm, Simon, Viviana, Zuliani-Alvarez, Lorena, Fontoura, Beatriz M A, Rosenberg, Brad R, Krogan, Nevan J, Martinez-Sobrido, Luis, García-Sastre, Adolfo, Miorin, Lisa

المساهمون: Kehrer, Thoma, Cupic, Anastasija, Ye, Chengjin, Yildiz, Soner, Bouhaddou, Mehdi, Crossland, Nicholas A, Barrall, Erika A, Cohen, Phillip, Tseng, Anna, Çağatay, Tolga, Rathnasinghe, Raveen, Flores, Daniel, Jangra, Sonia, Alam, Fahmida, Mena, Ignacio, Aslam, Sadaf, Saqi, Anjali, Rutkowska, Magdalena, Ummadi, Manisha R, Pisanelli, Giuseppe, Richardson, R Blake, Veit, Ethan C, Fabius, Jacqueline M, Soucheray, Margaret, Polacco, Benjamin J, Ak, Baran, Marin, Arturo, Evans, Matthew J, Swaney, Danielle L, Gonzalez-Reiche, Ana S, Sordillo, Emilia M, van Bakel, Harm, Simon, Viviana, Zuliani-Alvarez, Lorena, Fontoura, Beatriz M A, Rosenberg, Brad R, Krogan, Nevan J, Martinez-Sobrido, Lui, García-Sastre, Adolfo, Miorin, Lisa

مصطلحات موضوعية: ORF6, Omicron variant, SARS-CoV-2, SARS-CoV-2 pathogenesi, interferon, mRNA export, nuclear import, nucleocytoplasmic trafficking, virus-host interaction

الوصف: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:001098076000001; volume:31; issue:10; firstpage:1668; lastpage:1684; numberofpages:17; journal:CELL HOST & MICROBE; https://hdl.handle.net/11588/943187Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85173049322; https://www.cell.com/cell-host-microbe/fulltext/S1931-3128Test(23)00328-1?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S1931312823003281?showall=trueTest

الإتاحة: https://doi.org/10.1016Test/j.chom.2023.08.003
https://hdl.handle.net/11588/943187Test
https://www.cell.com/cell-host-microbe/fulltext/S1931-3128Test(23)00328-1?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S1931312823003281?showall=trueTest

المؤلفون: Chen, Zhen, Shiozaki, Momoko, Haas, Kelsey M., Skinner, Will M., Zhao, Shumei, Guo, Caiying, Polacco, Benjamin J., Yu, Zhiheng, Krogan, Nevan J., Lishko, Polina V., Kaake, Robyn M., Vale, Ronald D., Agard, David A.

المصدر: Cell, 186(23), 5041-5053.e19, (2023-11-09)

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الوصف: To understand the molecular mechanisms of cellular pathways, contemporary workflows typically require multiple techniques to identify proteins, track their localization, and determine their structuresinvitro. Here, we combined cellularcryoelectron tomography(cryo-ET) and AlphaFold2 modeling to address these questions and understand how mammalian sperm are builtin situ. Our cellular cryo-ET and subtomogram averaging provided 6.0-Å reconstructions of axonemal microtubule structures. The well-resolvedtertiary structuresallowed us to unbiasedly match sperm-specific densities with 21,615 AlphaFold2-predicted protein models of the mouseproteome. We identifiedTektin5,CCDC105, andSPACA9as novel microtubule-associated proteins. These proteins form an extensive interaction network crosslinking the lumen of axonemal doublet microtubules, suggesting their roles in modulating the mechanical properties of the filaments. Indeed,Tekt5−/−sperm possess more deformed flagella with 180° bends. Together, our studies presented a cellular visualproteomicsworkflow and shed light on theinvivo functions of Tektin 5. ; We are grateful to members of the Agard and Vale laboratories for the discussions and critical reading of the manuscript. We thank Xiaowei Zhao, Shixin Yang, and Rui Yan from the CryoEM Facility at the Janelia Research Campus for their assistance with data collection. We thank Zanlin Yu and Hao Wu at UCSF for their suggestions on sample processing and model building. We thank Garrett Greenan, Shawn Zheng, and Sam Li at UCSF for discussions on cryo-ET data processing. We thank Willy Wrigger from Old Dominion University for his input and suggestions on the SITUS package. EM data processing utilized computing resources at both the workstations at the CryoEM Facility at the Janelia Research Campus and the UCSF HPC Wynton cluster. We also thank David Bulkley, Glenn Gilbert, and Matt Harrington from the UCSF cryo-EM facility for their discussion on data collection and processing. We also thank Colin Morrow, Gillian Harris, ...

العلاقة: https://doi.org/10.1016Test/j.cell.2023.09.017; oai:authors.library.caltech.edu:1q9tv-0zd54

الإتاحة: https://doi.org/10.1016Test/j.cell.2023.09.017

المؤلفون: Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Polacco, Benjamin J., Thorne, Lucy G., Ummadi, Manisha R., Ye, Chengjin, Rosales, Romel, Pelin, Adrian, Batra, Jyoti, Jang, Gwendolyn M., Xu, Jiewei, Moen, Jack M., Richards, Alicia L., Zhou, Yuan, Harjai, Bhavya, Stevenson, Erica, Rojc, Ajda, Ragazzini, Roberta, Whelan, Matthew V.X., Furnon, Wilhelm, De Lorenzo, Giuditta, Cowton, Vanessa, Syed, Abdullah M., Ciling, Alison, Deutsch, Noa, Pirak, Daniel, Dowgier, Giulia, Mesner, Dejan, Turner, Jane L., McGovern, Briana L., Rodriguez, M. Luis, Leiva-Rebollo, Rocio, Dunham, Alistair S., Zhong, Xiaofang, Eckhardt, Manon, Fossati, Andrea, Liotta, Nicholas F., Kehrer, Thomas, Cupic, Anastasija, Rutkowska, Magdalena, Mena, Ignacio, Aslam, Sadaf, Hoffert, Alyssa, Foussard, Helene, Olwal, Charles Ochieng’, Huang, Weiqing, Zwaka, Thomas, Pham, John, Lyons, Molly, Donohue, Laura

المصدر: Cell ; volume 186, issue 21, page 4597-4614.e26 ; ISSN 0092-8674

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الإتاحة: https://doi.org/10.1016Test/j.cell.2023.08.026
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