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.
National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
Cell Rep. 2024 Aug 27;43(8):114608. doi: 10.1016/j.celrep.2024.114608. Epub 2024 Aug 8.
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.
泛素化对于蛋白酶体介导的 IRF3 周转至关重要，IRF3 是介导抗病毒先天免疫反应的核心因子。然而，IRF3 泛素化的时空调节对于先天免疫的精确激活和及时解决仍然不清楚。在这里，我们确定 BRCA1 相关蛋白-1（BAP1）和泛素蛋白连接酶 E3C（UBE3C）作为关键的去泛素酶和泛素酶，用于在病毒感染期间控制 IRF3 稳定性的时间。在早期阶段，BAP1 主导并去除核内 IRF3 的 K48 连接泛素化，防止其蛋白酶体降解，并促进有效的干扰素（IFN）-β产生。在晚期阶段，由 IFN-β 诱导的 E3 连接酶 UBE3C 特异性介导 IRF3 泛素化并促进其蛋白酶体降解。总的来说，与 BAP1 和 UBE3C 的顺序相互作用在先天反应期间控制 IRF3 的稳定性，确保有效的病毒清除和炎症解决。我们的发现提供了对先天信号时空控制的深入了解，并为病毒感染提供了潜在的干预措施。
