Negative Control of TLR3 Signaling by TICAM1 Down-Regulation
Negative Control of TLR3 Signaling by TICAM1 Down-Regulation
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DOI：
10.1165/rcmb.2011-0340oc
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发表时间：
2012-05-01
影响因子：
6.4
通讯作者：
Chen, Yin
中科院分区：
文献类型：
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作者：
Tao, Shasha;Zhu, Lingxiang;Chen, Yin
Toll-IL-1受体（TIR）结构域的衔接分子-1（TICAM 1，也称为TRIF）是TLR 3和TLR 4信号通路中的重要衔接蛋白，介导促炎细胞因子和IFN反应。据报道，外源性病毒蛋白酶或内源性半胱天冬酶和蛋白酶体对TICAM 1的负调节可关闭TICAM 1介导的信号传导。在这项研究中，我们发现TICAM 1的下调，而不是在这个信号通路中的其他组件，发生在由双链RNA或人鼻病毒（RV）感染诱导的TLR 3激活的气道上皮细胞和各种其他细胞类型的自然过程。TICAM 1是IFN表达所必需的，TICAM 1的缺失显著提高了RV的产生。由先前的双链RNA处理引起的TICAM 1蛋白表达的低水平导致在额外处理后缺乏IFN产生，表明受体脱敏。在后续研究中，发现TICAM 1下调依赖于TLR 3，但不依赖于RIG 1、MDA 5或PKR，并且似乎在治疗后受到调节。蛋白酶体和半胱天冬酶抑制剂均不能阻止TICAM 1下调。相反，溶酶体介导的过程似乎参与，这表明一种新的机制，是不同于以往的报告。总之，TICAM 1下调是TLR 3激活的重要步骤，其功能是阻止TLR 3介导的IFN产生。
Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM1, also called TRIF) is an important adaptor protein in TLR3 and TLR4 signaling pathways that mediate proinflammatory cytokine and IFN responses. Negative regulation of TICAM1 by exogenous viral protease or by endogenous caspase and proteasome have been reported to shut down TICAM1-mediated signaling. In this study, we discovered that down-regulation of TICAM1, but not other components in this signaling pathway, occurred in a natural process of TLR3 activation induced by double-stranded RNA or human rhinovirus (RV) infection in airway epithelial cells and various other cell types. TICAM1 was essential for IFN expression, and the loss of TICAM1 significantly elevated RV production. The low level of TICAM1 protein expression, caused by the prior double-stranded RNA treatment, led to a lack of IFN production upon additional treatment, suggesting receptor desensitization. In follow-up studies, TICAM1 down-regulation was found to be dependent on TLR3 but not RIG1, MDA5, or PKR and appeared to be regulated post-translationally. Neither proteasome nor caspase inhibitors could prevent TICAM1 down-regulation. Instead, a lysosome-mediated process appeared to be involved, suggesting a novel mechanism that is different from previous reports. In conclusion, TICAM1 down-regulation is an essential step in TLR3 activation, and its function is to stop TLR3-mediated IFN production.