MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors.
MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors.
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DOI：
10.1186/1741-7007-10-44
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发表时间：
2012-05-24
期刊：
影响因子：
5.4
通讯作者：
Arnoult D
中科院分区：
文献类型：
--
作者：
Castanier C;Zemirli N;Portier A;Garcin D;Bidère N;Vazquez A;Arnoult D
在病毒感染期间，细胞内RIG-I样受体（RLR）感测病毒RNA并通过线粒体抗病毒信号传导衔接子MAVS（也称为IPS-1、Cardif和VISA）发出信号，其激活分别通过转录因子IRF 3/IRF 7和NF-κB触发I型干扰素（IFN）和促炎细胞因子的快速产生。虽然MAVS对于这种信号传导是必不可少的，并且已知通过支架蛋白NEMO和磷酸化IRF 3的蛋白激酶TBK 1来操作，但其作用和调节机制仍不清楚。我们在这里报告说，RLR激活触发MAVS泛素化赖氨酸7和10的E3泛素连接酶TRIM 25，并标志着它的蛋白酶体降解伴随着下游信号。用蛋白酶体抑制剂抑制这种MAVS降解不会影响NF-κB信号传导，但会阻碍IRF 3活化，并且NEMO和TBK 1（I型IFN产生中的两种必需介质）保留在线粒体中。这些结果表明，MAVS作为募集平台，组装涉及NEMO和TBK 1的信号传导复合物，并且蛋白酶体介导的MAVS降解是将信号传导复合物释放到胞质溶胶中所必需的，从而允许IRF 3被TBK 1磷酸化。
During a viral infection, the intracellular RIG-I-like receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear. We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-κB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria. These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.
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