HDAC5 enhances IRF3 activation and is targeted for degradation by protein C6 from orthopoxviruses including Monkeypox virus and Variola virus
Yongxu Lu,
Yiqi Zhao,
Chen Gao,
Shreehari Suresh,
Jinghao Men,
Amelia Sawyers,
Geoffrey L. Smith
Affiliations
Yongxu Lu
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Chinese Academy of Medical Sciences-Oxford Institute, University of Oxford, Oxford, UK; Corresponding author
Yiqi Zhao
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Chinese Academy of Medical Sciences-Oxford Institute, University of Oxford, Oxford, UK
Chen Gao
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
Shreehari Suresh
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
Jinghao Men
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
Amelia Sawyers
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
Geoffrey L. Smith
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; The Pirbright Institute, Surrey, UK; Chinese Academy of Medical Sciences-Oxford Institute, University of Oxford, Oxford, UK; Corresponding author
Summary: 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.
