Abstract：
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.
摘要：
泛素化对于IRF3的蛋白酶体周转至关重要，IRF3是介导抗病毒先天性免疫反应的中心因子。然而,IRF3泛素化对先天免疫的精确激活和及时解决的时空调控仍不清楚.这里,我们将BRCA1相关蛋白-1(BAP1)和泛素蛋白连接酶E3C(UBE3C)鉴定为病毒感染期间IRF3稳定性的关键去泛素酶和泛素酶.在早期阶段,BAP1在细胞核中占主导地位并去除K48连接的IRF3泛素化，防止其蛋白酶体降解并促进有效的干扰素（IFN）-β生产。在后期阶段,E3连接酶UBE3C,由IFN-β诱导，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的顺序相互作用决定了先天反应过程中IRF3的稳定性，确保有效的病毒清除和炎症的解决。我们的发现提供了对先天信号的时间控制的见解，并提出了病毒感染的潜在干预措施。
