TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity
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DOI：
10.1038/nature05732
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发表时间：
2007-04-19
期刊：
影响因子：
64.8
通讯作者：
Jung, Jae U.
中科院分区：
文献类型：
--
作者：
Gack, Michaela U.;Shin, Young C.;Jung, Jae U.
视黄酸诱导基因-I （RIG-I，也称为DDX58）是一种胞质病毒RNA受体，可与MAVS（也称为VISA、IPS-1或Cardif）相互作用，诱导I型干扰素介导的宿主保护性先天免疫对抗病毒感染（1-6）。此外，tripartite motif （TRIM）蛋白家族的成员，包括一个RING-finger结构域、一个B box/coil -coil结构域和一个SPRY结构域，参与多种细胞过程，包括细胞增殖和抗病毒活性(7)。在这里，我们报道了rig - 1的氨基末端caspase募集结构域（CARDs）在哺乳动物细胞中被TRIM25诱导发生强大的泛素化。TRIM25的羧基末端SPRY结构域与rig - 1的n端卡相互作用；这种相互作用有效地将Lys 63连接的泛素片段传递到RIG-I的n端卡，导致RIG-I下游信号活动显著增加。RIG-I的Lys 172残基对于trim25介导的高效泛素化和MAVS结合以及RIG-I诱导抗病毒信号转导的能力至关重要。此外，基因靶向研究表明，TRIM25不仅对RIG-I泛素化至关重要，而且对RIG-I介导的干扰素β产生和RNA病毒感染的抗病毒活性也至关重要。因此，我们证明TRIM25 E3泛素连接酶可诱导Lys 63-linked RIG-I泛素化，这对于胞质RIG-I信号通路引发宿主抗病毒先天免疫至关重要。
Retinoic-acid- inducible gene-I (RIG-I; also called DDX58) is a cytosolic viral RNA receptor that interacts with MAVS ( also called VISA, IPS-1 or Cardif) to induce type I interferon-mediated host protective innate immunity against viral infection(1-6). Furthermore, members of the tripartite motif ( TRIM) protein family, which contain a cluster of a RING-finger domain, a B box/coiled-coil domain and a SPRY domain, are involved in various cellular processes, including cell proliferation and antiviral activity(7). Here we report that the amino-terminal caspase recruitment domains (CARDs) of RIG-I undergo robust ubiquitination induced by TRIM25 in mammalian cells. The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity. The Lys 172 residue of RIG-I is critical for efficient TRIM25-mediated ubiquitination and for MAVS binding, as well as the ability of RIG-I to induce antiviral signal transduction. Furthermore, gene targeting demonstrates that TRIM25 is essential not only for RIG-I ubiquitination but also for RIG-I-mediated interferon-beta production and antiviral activity in response to RNA virus infection. Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity.