Inhibition of mRNA nuclear export promotes SARS- CoV- pathogenesis

• 成果类型: Article
• 署名作者: Mei, Menghan; Cupic, Anastasija; Miorin, Lisa; Ye, Chengjin; Cagatay, Tolga; Zhang, Ke; Patel, Komal; Wilson, Natalie; McDonald, W. Hayes; Crossland, Nicholas A.; Lo, Ming; Rutkowska, Magdalena; Aslam, Sadaf; Mena, Ignacio; Martinez-Sobrido, Luis; Ren, Yi; Garcia-Sastre, Adolfo; Fontoura, Beatriz M. A.
• 署名单位: Vanderbilt University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Texas Biomedical Research Institute; University of Texas System; University of Texas Southwestern Medical Center; Chinese Academy of Sciences; Shanghai Institute of Immunity and Infection, CAS; Vanderbilt University; Vanderbilt University; Boston University; Boston University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Scripps Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9788
• DOI: 10.1073/pnas.2314166121
• 发表日期: 2024-05-23
• 关键词: host protein-synthesis; nonstructural protein-1; pathogenicity factor; nsp1; sars-cov-2; machinery

摘要

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 Nsp1mediated 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 Nsp1mediated 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 Nsp1mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS - CoV - 2.