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Herein, analysis of protein and gene expression in human antigen-presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. CIITA downregulation is independent of the proteolytic activity of NSP5, and rather, NSP5 delivers HDAC2 to the transcription factor IRF3 at an IRF-binding site within the CIITA promoter. Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response.<\/jats:p>","DOI":"10.1242\/jcs.262172","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T08:11:26Z","timestamp":1714378286000},"source":"Crossref","is-referenced-by-count":11,"title":["SARS-CoV-2 NSP5 antagonizes MHC II expression by subverting histone deacetylase 2"],"prefix":"10.1242","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6039-2921","authenticated-orcid":false,"given":"Nima","family":"Taefehshokr","sequence":"first","affiliation":[{"name":"Immunity and Inflammation Centre, The University of Western Ontario 1 Department of Microbiology and Immunology, and the Western Infection , , London, Ontario , Canada N6A 5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Lac","sequence":"additional","affiliation":[{"name":"Immunity and Inflammation 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