SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.

Autor:	Higgins CA; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Department of Microbiology, New York University Langone Health , New York, New York, USA.; Vilcek Graduate School for Biomedical Sciences, New York University Langone Health , New York, New York, USA., Nilsson-Payant BE; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Bonaventure B; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Kurland AP; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Ye C; Texas Biomedical Research Institute , San Antonio, Texas, USA., Yaron TM; Meyer Cancer Center, Weill Cornell Medicine , New York, New York, USA.; Englander Institute for Precision Medicine, Institute for Computational Biomedicine Weill Cornell Medicine , New York, New York, USA.; Columbia University Vagelos College of Physicians and Surgeons , New York, New York, USA., Johnson JL; Meyer Cancer Center, Weill Cornell Medicine , New York, New York, USA.; Department of Cell Biology, Harvard Medical School , Boston, Massachusetts, USA.; Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts, USA., Adhikary P; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Golynker I; Department of Microbiology, New York University Langone Health , New York, New York, USA., Panis M; Department of Microbiology, New York University Langone Health , New York, New York, USA., Danziger O; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Rosenberg BR; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA., Cantley LC; Meyer Cancer Center, Weill Cornell Medicine , New York, New York, USA.; Department of Cell Biology, Harvard Medical School , Boston, Massachusetts, USA.; Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts, USA., Martínez-Sobrido L; Texas Biomedical Research Institute , San Antonio, Texas, USA., tenOever B; Department of Microbiology, New York University Langone Health , New York, New York, USA., Johnson JR; Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York, USA.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai , New York, New York, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2023 Aug 31; Vol. 14 (4), pp. e0100723. Date of Electronic Publication: 2023 Jun 22.
DOI:	10.1128/mbio.01007-23
Abstrakt:	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. IMPORTANCE SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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