TRIM11 negatively regulates IFNβ production and antiviral activity by targeting TBK1.
TRIM11 negatively regulates IFNβ production and antiviral activity by targeting TBK1.
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DOI：
10.1371/journal.pone.0063255
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kwon KS
中科院分区：
文献类型：
--
作者：
Lee Y;Song B;Park C;Kwon KS
先天免疫反应是宿主抵御病毒和细菌感染的一种防御机制。I型干扰素（IFNα/β）在先天免疫中起重要作用。如果在正常条件下和免疫反应期间不严格调节，IFN的产生可能会变得异常，导致炎症和自身免疫性疾病。在这项研究中，我们发现TRIM11 （tripartite motif containing 11）是IFNβ产生的一个新的负调控因子。TRIM11的异位表达降低了由poly （I:C）刺激或过度表达RIG-I（维甲酸诱导基因-I）信号级联成分RIG-IN （RIG-I的组成活性形式），MAVS（线粒体抗病毒信号蛋白）或TBK1（罐结合激酶-1）引起的IFNβ启动子活性。相反，TRIM11敲低可增强这些刺激诱导的IFNβ启动子活性。此外，TRIM11过表达抑制IRF3的磷酸化和二聚化以及IFNβ mRNA的表达。相反，TRIM11敲除增加了IRF3磷酸化和IFNβ mRNA的表达。我们还发现TRIM11和TBK1 （RIG-I通路中磷酸化IRF3的关键激酶）分别通过CC和CC2结构域相互作用。这种相互作用在TBK1接头蛋白、NAP1 （NF-κB活化激酶相关蛋白-1）、SINTBAD（类似NAP1 TBK1接头）或TANK （TRAF家族成员相关NF-κB激活因子）存在时增强。与其在rig - i介导的IFNβ信号传导中的抑制作用一致，TRIM11过表达增强了病毒的感染性，而TRIM11敲低则产生相反的效果。总之，我们的研究结果表明TRIM11通过靶向TBK1信号复合物抑制rig - i介导的IFNβ产生。
The innate immune response is a host defense mechanism against infection by viruses and bacteria. Type I interferons (IFNα/β) play a crucial role in innate immunity. If not tightly regulated under normal conditions and during immune responses, IFN production can become aberrant, leading to inflammatory and autoimmune diseases. In this study, we identified TRIM11 (tripartite motif containing 11) as a novel negative regulator of IFNβ production. Ectopic expression of TRIM11 decreased IFNβ promoter activity induced by poly (I:C) stimulation or overexpression of RIG-I (retinoic acid-inducible gene-I) signaling cascade components RIG-IN (constitutively active form of RIG-I), MAVS (mitochondrial antiviral signaling protein), or TBK1 (TANK-binding kinase-1). Conversely, TRIM11 knockdown enhanced IFNβ promoter activity induced by these stimuli. Moreover, TRIM11 overexpression inhibited the phosphorylation and dimerization of IRF3 and expression of IFNβ mRNA. By contrast, TRIM11 knockdown increased the IRF3 phosphorylation and IFNβ mRNA expression. We also found that TRIM11 and TBK1, a key kinase that phosphorylates IRF3 in the RIG-I pathway, interacted with each other through CC and CC2 domain, respectively. This interaction was enhanced in the presence of the TBK1 adaptor proteins, NAP1 (NF-κB activating kinase-associated protein-1), SINTBAD (similar to NAP1 TBK1 adaptor) or TANK (TRAF family member-associated NF-κB activator). Consistent with its inhibitory role in RIG-I-mediated IFNβ signaling, TRIM11 overexpression enhanced viral infectivity, whereas TRIM11 knockdown produced the opposite effect. Collectively, our results suggest that TRIM11 inhibits RIG-I-mediated IFNβ production by targeting the TBK1 signaling complex.
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