DUBA: A deubiquitinase that regulates type I interferon production
DUBA: A deubiquitinase that regulates type I interferon production
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DOI：
10.1126/science.1145918
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发表时间：
2007-12-07
期刊：
影响因子：
56.9
通讯作者：
Dixit, Vishva M.
中科院分区：
文献类型：
--
作者：
Kayagaki, Nobuhiko;Phung, Qui;Dixit, Vishva M.
I型干扰素（IFN-I）的产生是由先天免疫系统的模式识别受体（PRR）触发的关键宿主防御。去泛素化酶A（杜巴）是一种含有卵巢肿瘤结构域的去泛素化酶，在基于小干扰RNA的筛选中被发现作为IFN-I产生的调节剂。杜巴的减少增强了PRR诱导的IFN-I反应，而杜巴的异位表达具有匡威的效果。杜巴结合肿瘤坏死因子受体相关因子3（TRAF 3），这是一种IFN-I应答所必需的衔接蛋白。TRAF 3是一种E3泛素连接酶，优先组装赖氨酸-63连接的多聚泛素链。杜巴选择性地切割TRAF 3上的赖氨酸-63-连接的多聚泛素链，导致其从含有TANK结合激酶1的下游信号复合物中解离。杜巴内的离散泛素相互作用基序是TRAF 3有效去泛素化和IFN-I最佳抑制所必需的。我们的数据确定杜巴是先天免疫反应的负调节因子。
Production of type I interferon (IFN-I) is a critical host defense triggered by pattern-recognition receptors (PRRs) of the innate immune system. Deubiquitinating enzyme A ( DUBA), an ovarian tumor domain-containing deubiquitinating enzyme, was discovered in a small interfering RNA-based screen as a regulator of IFN-I production. Reduction of DUBA augmented the PRR-induced IFN-I response, whereas ectopic expression of DUBA had the converse effect. DUBA bound tumor necrosis factor receptor-associated factor 3 ( TRAF3), an adaptor protein essential for the IFN-I response. TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANKbinding kinase 1. A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. Our data identify DUBA as a negative regulator of innate immune responses.