I型干扰素(IFN)信号通路的严格控制对于维持宿主的先天免疫反应至关重要。信号分子的泛素化和去泛素化对信号转导至关重要。去泛素酶泛素特异性蛋白19(USP19)已知参与去泛素化Beclin1,TRAF3和TRIF以下调I型IFN信号传导。这里,SIAH1是一种参与多细胞通路的细胞E3泛素连接酶,是病毒介导的I型IFN信号的有效正调节剂,通过靶向USP19维持抗病毒免疫应答内的稳态。在病毒感染的早期阶段,稳定的SIAH1直接与USP19相互作用,并同时介导USP19的489、490和610残基的K27连接的泛素化,以进行蛋白酶体降解。此外,我们发现USP19与MAVS特异性相互作用,去泛素化K63连接的泛素化MAVS对I型IFN信号传导进行负调控.最终,我们发现SIAH1介导的USP19降解逆转了USP19介导的MAVS去泛素化,Beclin1、TRAF3和TRIF,导致抗病毒免疫反应的激活。一起来看,这些发现为USP19和SIAH1的分子机制提供了新的见解,并表明SIAH1在抗病毒免疫应答和稳态中的关键作用。
Tight control of the type I interferon (IFN) signaling pathway is critical for maintaining host innate immune responses, and the ubiquitination and deubiquitination of signaling molecules are essential for signal transduction. Deubiquitinase ubiquitin-specific protein 19 (
USP19) is known to be involved in deubiquitinating Beclin1, TRAF3, and TRIF for downregulation of the type I IFN signaling. Here, we show that SIAH1, a cellular E3 ubiquitin ligase that is involved in multicellular pathway, is a potent positive regulator of virus-mediated type I IFN signaling that maintains homeostasis within the antiviral immune response by targeting USP19. In the early stages of virus infection, stabilized SIAH1 directly interacts with the
USP19 and simultaneously mediates K27-linked ubiquitination of 489, 490, and 610 residues of
USP19 for proteasomal degradation. Additionally, we found that USP19 specifically interacts with MAVS and deubiquitinates K63-linked ubiquitinated MAVS for negative regulation of type I IFN signaling. Ultimately, we identified that SIAH1-mediated degradation of
USP19 reversed
USP19-mediated deubiquitination of MAVS, Beclin1, TRAF3, and TRIF, resulting in the activation of antiviral immune responses. Taken together, these findings provide new insights into the molecular mechanism of
USP19 and SIAH1, and suggest a critical role of SIAH1 in antiviral immune response and homeostasis.