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

• Published in: Nature communications Vol. 12; no. 1; pp. 6602 - 17
• Main Authors: Yoo, Ji-Seung, Sasaki, Michihito, Cho, Steven X., Kasuga, Yusuke, Zhu, Baohui, Ouda, Ryota, Orba, Yasuko, de Figueiredo, Paul, Sawa, Hirofumi, Kobayashi, Koichi S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/89; 13/95; 14; 14/1; 38; 38/77; 38/89; 38/91; 631/250/21/324/1509; 631/250/255/2514; 96; Antigen presentation; Antigens; Antiviral drugs; Cell Line; Cell lines; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - pathology; COVID-19 - virology; Critical components; Epithelial cells; Epithelium; Female; Gene expression; Gene Expression Regulation; Genes, MHC Class I - immunology; Humanities and Social Sciences; Humans; Interferon; Interferon regulatory factor 1; Interferon Regulatory Factor-1 - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Middle Aged; multidisciplinary; Nuclear transport; SARS-CoV-2 - genetics; SARS-CoV-2 - isolation & purification; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Stat1 protein; STAT1 Transcription Factor - antagonists & inhibitors; Transcription; Viral diseases; Viral infections; Viral Proteins - immunology; Viral Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• 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. 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.