The deubiquitinase BAP1 and E3 ligase UBE3C sequentially target IRF3 to activate and resolve the antiviral innate immune response
Xiang Liu,
Likun Cui,
Yijie Tao,
Simo Xia,
Jin Hou,
Xuetao Cao,
Sheng Xu
Affiliations
Xiang Liu
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Department of Respiratory Disease, Affiliated Xihu Hospital, Hangzhou Medical College, Hangzhou 310013, China
Likun Cui
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Yijie Tao
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Simo Xia
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Jin Hou
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Xuetao Cao
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, College of Life Science, Nankai University, Tianjin 30071, China; Corresponding author
Sheng Xu
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Corresponding author
Summary: Ubiquitination is essential for the proteasomal turnover of IRF3, the central factor mediating the antiviral innate immune response. However, the spatiotemporal regulation of IRF3 ubiquitination for the precise activation and timely resolution of innate immunity remains unclear. Here, we identified BRCA1-associated protein-1 (BAP1) and ubiquitin-protein ligase E3C (UBE3C) as the key deubiquitinase and ubiquitinase for temporal control of IRF3 stability during viral infection. In the early stage, BAP1 dominates and removes K48-linked ubiquitination of IRF3 in the nucleus, preventing its proteasomal degradation and facilitating efficient interferon (IFN)-β production. In the late stage, E3 ligase UBE3C, induced by IFN-β, specifically mediates IRF3 ubiquitination and promotes its proteasomal degradation. Overall, the sequential interactions with BAP1 and UBE3C govern IRF3 stability during innate response, ensuring effective viral clearance and inflammation resolution. Our findings provide insights into the temporal control of innate signaling and suggest potential interventions in viral infection.
