Toll-like receptor (TLR)-mediated signaling are critical for host defense against pathogen invasion. However, excessive responses would cause harmful damages to the host. Here we show that deficiency of the E3 ubiquitin ligase TRIM32 increases poly(I:C)- and LPS-induced transcription of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines in both primary mouse immune cells and in mice. Trim32^-/- mice produced higher levels of serum inflammatory cytokines and were more sensitive to loss of body weight and inflammatory death upon Salmonella typhimurium infection. TRIM32 interacts with and mediates the degradation of TRIF, a critical adaptor protein for TLR3/4, in an E3 activity-independent manner. TRIM32-mediated as well as poly(I:C)- and LPS-induced degradation of TRIF is inhibited by deficiency of TAX1BP1, a receptor for selective autophagy. Furthermore, TRIM32 links TRIF and TAX1BP1 through distinct domains. These findings suggest that TRIM32 negatively regulates TLR3/4-mediated immune responses by targeting TRIF to TAX1BP1-mediated selective autophagic degradation.

Toll样受体（TLR）介导的信号对于宿主防御病原体入侵至关重要。但是，过度的响应会对主机造成有害损害。在这里，我们显示E3泛素连接酶TRIM32的缺乏增加了原代小鼠免疫细胞和小鼠体内诸如I型干扰素（IFN）和促炎细胞因子等下游基因的poly（I：C）和LPS诱导的转录。Trim32 ^-/-小鼠产生更高水平的血清炎性细胞因子，对鼠伤寒沙门氏菌引起的体重减轻和炎性死亡更敏感感染。TRIM32以E3活性独立的方式与TRIF（TLR3 / 4的关键衔接蛋白）相互作用并介导其降解。TRIM32介导的以及聚（I：C）和LPS诱导的TRIF降解受选择性自噬受体TAX1BP1缺乏的抑制。此外，TRIM32通过不同的域链接TRIF和TAX1BP1。这些发现表明，TRIM32通过将TRIF靶向TAX1BP1介导的选择性自噬降解来负调节TLR3 / 4介导的免疫反应。