Inhibition of mRNA nuclear export promotes SARS-CoV-2 pathogenesis.

Autor:	Mei M; Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232., Cupic A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Miorin L; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Ye C; Texas Biomedical Research Institute, San Antonio, TX 78227., Cagatay T; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Zhang K; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China., Patel K; Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.; Arpirnaut Program, Vanderbilt University School of Medicine, Nashville, TN 37232., Wilson N; Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232., McDonald WH; Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.; Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232., Crossland NA; Comparative Pathology Laboratory, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02215.; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118., Lo M; Comparative Pathology Laboratory, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02215., Rutkowska M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Aslam S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Mena I; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Martinez-Sobrido L; Texas Biomedical Research Institute, San Antonio, TX 78227., Ren Y; Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232., García-Sastre A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Fontoura BMA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 28; Vol. 121 (22), pp. e2314166121. Date of Electronic Publication: 2024 May 20.
DOI:	10.1073/pnas.2314166121
Abstrakt:	The nonstructural protein 1 (Nsp1) of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a virulence factor that targets multiple cellular pathways to inhibit host gene expression and antiviral response. However, the underlying mechanisms of the various Nsp1-mediated functions and their contributions to SARS-CoV-2 virulence remain unclear. Among the targets of Nsp1 is the mRNA (messenger ribonucleic acid) export receptor NXF1-NXT1, which mediates nuclear export of mRNAs from the nucleus to the cytoplasm. Based on Nsp1 crystal structure, we generated mutants on Nsp1 surfaces and identified an acidic N-terminal patch that is critical for interaction with NXF1-NXT1. Photoactivatable Nsp1 probe reveals the RNA Recognition Motif (RRM) domain of NXF1 as an Nsp1 N-terminal binding site. By mutating the Nsp1 N-terminal acidic patch, we identified a separation-of-function mutant of Nsp1 that retains its translation inhibitory function but substantially loses its interaction with NXF1 and reverts Nsp1-mediated mRNA export inhibition. We then generated a recombinant (r)SARS-CoV-2 mutant on the Nsp1 N-terminal acidic patch and found that this surface is key to promote NXF1 binding and inhibition of host mRNA nuclear export, viral replication, and pathogenicity in vivo. Thus, these findings provide a mechanistic understanding of Nsp1-mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS-CoV-2. Competing Interests: Competing interests statement:A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, and Pfizer, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York.
Databáze:	MEDLINE
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