SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis

Nat Commun. 2021 Nov 15;12(1):6602. doi: 10.1038/s41467-021-26910-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / genetics
  • COVID-19 / immunology*
  • COVID-19 / pathology
  • COVID-19 / virology
  • Cell Line
  • Female
  • Gene Expression Regulation
  • Genes, MHC Class I / immunology*
  • Humans
  • Interferon Regulatory Factor-1 / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Male
  • Middle Aged
  • SARS-CoV-2 / genetics*
  • SARS-CoV-2 / isolation & purification
  • STAT1 Transcription Factor / antagonists & inhibitors*
  • Signal Transduction
  • Viral Proteins / immunology
  • Viral Proteins / metabolism*


  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Intracellular Signaling Peptides and Proteins
  • NLRC5 protein, human
  • ORF6 protein, SARS-CoV-2
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Viral Proteins