HDAC5 enhances IRF3 activation and is targeted for degradation by protein C6 from orthopoxviruses including Monkeypox virus and Variola virus

Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function. [Display omitted] •HDAC5 promotes TRIF-mediated IRF3 activation•HDAC5 restricts multiple orthopoxviruses and is degraded during virus infection•Orthopoxvirus protein C6 induces HDAC5 degradation•Protein C6 binds directly to HDAC5 dimerization domain, thereby preventing dimerization HDAC5 enhances TRIF-mediated IRF3 activation and restricts several orthopoxviruses. Lu et al. show that the C6 protein of these orthopoxviruses induces degradation of HDAC5 and interacts directly with HDAC5 via the HDAC5 N-terminal dimerization domain.