Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3.
Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3.
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DOI：
10.1016/j.molcel.2009.09.037
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发表时间：
2009-10-23
期刊：
影响因子：
16
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Zeng W;Xu M;Liu S;Sun L;Chen ZJ
线粒体抗病毒信号蛋白（MAVS;也称为IPS-1，VISA和CARDIF）是针对RNA病毒的先天免疫应答所必需的。MAVS从与病毒RNA结合的胞质RIG-I样受体中转导信号，但MAVS如何激活下游转录因子（例如IRF 3）来诱导I型干扰素尚不清楚。我们已经建立了一个无细胞系统，其中来自病毒感染细胞的线粒体激活胞质溶胶中的IRF3。细胞质的分级导致Ubc5作为IRF3激活所需的泛素缀合酶（E2）的鉴定。使用可诱导的RNAi策略，我们证明了催化活性Ubc5是通过病毒感染激活IRF3所必需的。IRF3的激活还需要NEMO的两个泛素结合结构域。此外，我们发现，其K63R突变体的内源性泛素的替代废除IRF3的病毒激活，表明K63多聚泛素化在IRF3激活中起着关键作用。
The mitochondrial antiviral signaling protein (MAVS; also known as IPS-1, VISA and CARDIF) is essential for innate immune response against RNA viruses. MAVS transduces signals from the cytosolic RIG-I-like receptors, which bind to viral RNAs, but how MAVS activates downstream transcription factors such as IRF3 to induce type-I interferons is not well understood. We have established a cell-free system in which mitochondria derived from virus-infected cells activates IRF3 in the cytosol. Fractionation of the cytosol led to the identification of Ubc5 as a ubiquitin-conjugating enzyme (E2) required for IRF3 activation. Using an inducible RNAi strategy, we demonstrate that catalytically active Ubc5 is required for IRF3 activation by viral infection. The activation of IRF3 also requires two ubiquitin-binding domains of NEMO. Furthermore, we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation of IRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation.
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