E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3.
E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3.
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E3连接酶Nedd4l通过催化TRAF3的K29连接半胱氨酸泛素化促进抗病毒先天免疫
DOI：
10.1038/s41467-021-21456-1
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发表时间：
2021-02-19
影响因子：
16.6
通讯作者：
An H
中科院分区：
文献类型：
--
作者：
Gao P;Ma X;Yuan M;Yi Y;Liu G;Wen M;Jiang W;Ji R;Zhu L;Tang Z;Yu Q;Xu J;Yang R;Xia S;Yang M;Pan J;Yuan H;An H
泛素化是最常见的蛋白质翻译后修饰之一。在这里，我们发现E3连接酶Nedd 4l通过催化TRAF 3的K29连接的半胱氨酸泛素化来积极调节抗病毒免疫。在体外和体内，Nedd 4l的缺乏显著损害由病毒感染诱导的I型干扰素和促炎细胞因子的产生。Nedd 4l缺陷抑制TRAF 3的病毒诱导的泛素化，TRAF 3和TBK 1之间的结合，以及随后的TBK 1和IRF 3的磷酸化。Nedd 4l直接与TRAF 3相互作用并催化K29连接的Cys 56和Cys 124的泛素化，这两个半胱氨酸构成锌指，导致TRAF 3和E3连接酶，cIAP 1/2和HECTD 3之间的关联增强，并且还增加了TRAF 3的K48/K63连接的泛素化。Cys 56和Cys 124的突变减少了Nedd 4l催化的K29连接的泛素化，但增强了TRAF 3和E3连接酶之间的关联，支持Nedd 4l通过催化TRAF 3中半胱氨酸的泛素化来促进I型干扰素的产生。泛素化是一种普遍存在的翻译后修饰。在这里，作者显示了Nedd 4l通过促进TRAF 3的泛素化在调节抗病毒免疫中的关键作用，并继续显示Nedd 4l在体外和体内的破坏扰乱了抗病毒免疫应答。
Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3. Ubiquitination is a prevalent post translational modification. Here, the authors show a pivotal role for Nedd4l in the regulation of antiviral immunity via promotion of ubiquitination of TRAF3 and go on to show disruption of Nedd4l both in vitro and in vivo perturbs the antiviral immune response.