TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms
TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms
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TRIM38 通过两种顺序且不同的机制负向调节 TLR3/4 介导的先天免疫和炎症反应
DOI：
10.4049/jimmunol.1500859
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发表时间：
2015-11-01
影响因子：
4.4
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Hu, Ming-Ming;Xie, Xue-Qin;Shu, Hong-Bing
三分基序（TRIM）38是E3泛素连接酶，据报道其在某些细胞系中调节先天免疫和炎症反应中的信号传导。在这项研究中，我们发现Trim 38缺陷显著增加了免疫细胞和体内TLR 3和TLR 4介导的I型IFN和促炎细胞因子（如TNF-α、IL-1β和IL-6）的诱导。Trim 38缺陷还导致小鼠更容易受到多聚肌苷酸、LPS和鼠伤寒沙门氏菌引发的死亡。在机制上，TRIM 38催化K48连接的TLR 3/4衔接蛋白TIR结构域的多聚泛素化，该结构域含有在K228处诱导IFN-β的衔接子，并促进其在免疫细胞中的蛋白酶体降解。此外，Trim 38被I型IFN高度诱导，I型IFN随后通过介导Tab 2在溶酶体依赖性过程中的降解来负调节IFN-β致敏的免疫细胞中的TNF-α/IL-1β信号传导，但不调节未致敏的免疫细胞。这些结果表明，Trim 38负调节TLR 3/4介导的先天免疫和炎症反应的两个顺序和不同的机制。这项研究增加了我们对先天免疫反应如何在感染早期启动以抵御微生物入侵的理解，并在晚期有效终止以防止过度和有害的炎症反应。
Tripartite motif (TRIM)38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain–containing adapter-inducing IFN-β at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-α/IL-1β signaling in IFN-β–primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.