SARS-CoV-2 NSP5 Antagonizes MHC II Expression by Subverting Histone Deacetylase 2

• Published in: bioRxiv 2023-12
• Main Authors: Taefehshokr, Nima, Lac, Alex, Vrieze, Angela M, Dickson, Brandon H, Guo, Peter N, Jung, Catherine, Blythe, Eoin N, Fink, Corby, Aktar, Amena, Dikeakos, Jimmy D, Dekaban, Gregory A, Heit, Bryan
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Antigen presentation; Antigen-presenting cells; CD4 antigen; Cell activation; CIITA protein; COVID-19; Dendritic cells; Ectopic expression; Gene expression; HDAC2 protein; Histone deacetylase; Immune clearance; Interferon regulatory factor 3; Lymphocytes T; Macrophages; Major histocompatibility complex; Proteolysis; Severe acute respiratory syndrome coronavirus 2
• DOI: 10.1101/2023.02.10.528032

SARS-CoV-2 interferes with antigen presentation by downregulating MHC II on antigen presenting cells, but the mechanism mediating this process is unelucidated. 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. This downregulation of CIITA is independent of NSP5's proteolytic activity, but rather, NSP5 delivers HDAC2 to 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. Importance: SARS-CoV-2 alters the expression of many immunoregulatory proteins to limit and delay the host antiviral response, thereby producing a more severe and longer-lasting infection. Preventing and limiting the activation of helper T cells by reducing MHC II expression on antigen presenting cells is one of these strategies, but while this mechanism was identified early in the pandemic, the mechanism allowing SARS-CoV-2 to limit MHC II expression has remained unclear. Herein, we demonstrate that this occurs via a tripartite interaction between viral NSP5 and host HDAC2 and IRF3, where a complex of NSP5 and HDAC2 is recruited to IRF3 bound to the promoter of CIITA - the master regulator of MHC II expression - with the delivery of HDAC2 then mediating the deacetylation of the CIITA promoter and the suppression of MHC II expression.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Major revision, includes revisions to all text sections (abstract, introduction, results, discussion, materials and methods, etc), and includes new data in all figures, including the addition of a new figure (Figure 6). New co-author added. Supplemental materials also have updates (new primer sequences, updated figure S1, S2, and S3)