TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses
TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses
复制标题
TRIM14 抑制选择性自噬受体 p62 介导的 cGAS 降解，以促进先天免疫反应。
DOI：
10.1016/j.molcel.2016.08.025
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发表时间：
2016-10-06
期刊：
影响因子：
16
通讯作者：
Cui, Jun
中科院分区：
文献类型：
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作者：
Chen, Meixin;Meng, Qingcai;Cui, Jun
环GMP-AMP合酶（cGAS）是一种重要的DNA病毒传感器，其通过产生cGAMP来触发I型干扰素（IFN）信号传导以启动抗病毒免疫。然而，cGAS的翻译后调节在很大程度上仍然未知。我们报道了cGAS的K48连接的泛素化是p62依赖的选择性自噬降解的识别信号。I型IFN对TRIM 14的诱导通过募集USP 14以在赖氨酸（K）414处切割cGAS的泛素链来加速cGAS稳定化。TRIM14的敲除以cGAS依赖性方式损害单纯疱疹病毒1型（HSV-1）触发的抗病毒应答。由于I型IFN产生受损，Trim14（-/-）小鼠对致死性HSV-1感染高度易感。总之，我们的发现揭示了TRIM14-USP14产生的cGAS信号传导的正反馈回路，并提供了对先天免疫中自噬和I型IFN信号传导之间的串扰的见解。
Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14(-/-) mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.