Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26910-8
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Funding
- American Lung Association [LCD-507710]
- National Multiple Sclerosis Society
- CSTR
- TAM Genomics
- Japan Society for the Promotion of Science (JSPS) [18H06135, 20K21511, 19K23837, 21K15445, 19K16681]
- SENSHIN Medical Research Foundation
- Bristol Myers Squibb grant
- Takeda Science Foundation
- Kaketsu-ken foundation grant
- Kobayashi Foundation grant
- Japan Program for Infectious Diseases Research and Infrastructure from Japan Agency for Medical Research and Development (AMED) [JP 20wm022500]
- The Hitachi Global Foundation
- Grants-in-Aid for Scientific Research [21K15445, 20K21511, 18H06135, 19K16681, 19K23837] Funding Source: KAKEN
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The authors show that SARS-CoV-2 targets key transcriptional regulators of the MHC class I pathway to hinder antigen presentation, revealing an immune evasion mechanism that suppresses host immune response.
The presentation of viral antigens to T cells via the MHC molecules is a critical component of the host response to viral infection. Here the authors suggest SARS-CoV-2 possesses the immune evasion strategy against the MHC class I pathway by targeting key transcriptional regulators. The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.
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