E3 Ubiquitin Ligase Tripartite Motif 38 Negatively Regulates TLR-Mediated Immune Responses by Proteasomal Degradation of TNF Receptor-Associated Factor 6 in Macrophages
E3 Ubiquitin Ligase Tripartite Motif 38 Negatively Regulates TLR-Mediated Immune Responses by Proteasomal Degradation of TNF Receptor-Associated Factor 6 in Macrophages
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E3 泛素连接酶三联基序 38 通过巨噬细胞中 TNF 受体相关因子 6 的蛋白酶体降解负调节 TLR 介导的免疫反应
DOI：
10.4049/jimmunol.1103255
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发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Gao, Chengjiang
中科院分区：
文献类型：
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作者：
Zhao, Wei;Wang, Lijuan;Gao, Chengjiang
天然免疫细胞中TLR信号的激活对于清除入侵微生物至关重要。然而，不受控制的激活可能会导致自身免疫性和炎症性疾病。在这篇文章中，我们报道了通过靶向TNFR相关因子6(TRAF6)，三方基序(TRIM)38在TLR信号转导中作为负反馈调节因子。在巨噬细胞中，TLR以依赖于κB的方式诱导TRIM38的表达。小干扰核糖核酸下调TRIM38的表达可增强NF-κB和MAPKs的激活，增强促炎细胞因子的表达，而过表达的TRIM38则相反。作为E3连接酶，TRIM38与TRAF6结合，促进K48连接的多泛素化，导致TRAF6的蛋白酶体降解。在原代巨噬细胞中，TRIM38表达下调导致TRAF6蛋白水平升高。我们的发现定义了TRIM38的一个新功能，即通过蛋白酶体降解TRAF6来防止TLR过度诱导的炎症反应。
Activation of TLR signaling in the innate immune cells is critical for the elimination of invading microorganisms. However, uncontrolled activation may lead to autoimmune and inflammatory diseases. In this article, we report the identification of tripartite motif (TRIM) 38 as a negative feedback regulator in TLR signaling by targeting TNFR-associated factor 6 (TRAF6). TRIM38 was induced by TLR stimulation in an NF-κB–dependent manner in macrophages. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of NF-κB and MAPKs, and enhanced expression of proinflammatory cytokines, whereas overexpression of TRIM38 has an opposite effect. As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. Consistently, knockdown of TRIM38 expression resulted in higher protein level of TRAF6 in primary macrophages. Our findings defined a novel function for TRIM38 to prevent excessive TLR-induced inflammatory responses through proteasomal degradation of TRAF6.