RNF144A promotes antiviral responses by modulating STING ubiquitination
RNF144A promotes antiviral responses by modulating STING ubiquitination
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RNF144A通过调节STING泛素化促进抗病毒反应
DOI：
10.15252/embr.202357528
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发表时间：
2023-11
期刊：
影响因子：
7.7
通讯作者：
Bo Yang;Jinyong Pei;Chen Lu;Yi Wang;Mengyang Shen;Xiao Qin;Yulu Huang;Xi Yang;Xin Zhao-Xi
中科院分区：
文献类型：
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作者：
Bo Yang;Jinyong Pei;Chen Lu;Yi Wang;Mengyang Shen;Xiao Qin;Yulu Huang;Xi Yang;Xin Zhao-Xi
干扰素（IFN）基因刺激因子（STING，也称为MITA，ERIS，MPYS或TMEM 173）在DNA病毒或细胞溶质DNA触发的先天性免疫应答中起着重要作用。在这里，我们证明了RING-in-between RING（RBR）E3泛素连接酶家族成员RING-finger蛋白（RNF）144 A与STING相互作用，并促进其在K236处的K6-连接的泛素化，从而增强STING从ER到高尔基体和下游信号通路的易位。STING的K236 R突变体在促进先天免疫信号转导中显示出降低的活性。RNF 144 A的过表达上调HSV-1或胞质DNA诱导的免疫应答，而RNF 144 A表达的敲低具有相反的效果。此外，Rnf 144 a缺陷细胞表现出受损的DNA病毒或细胞溶质DNA触发的信号传导，并且RNF 144 A保护小鼠免受DNA病毒感染。相反，RNF 144 A不影响RNA病毒或胞质RNA触发的先天免疫应答。总之，我们的研究结果确定了一种新的DNA病毒或细胞溶质DNA触发的信号通路的正调节因子，以及一个在抗病毒反应期间对全功能STING重要的关键泛素化位点。
Stimulator of interferon (IFN) genes (STING, also named MITA, ERIS, MPYS, or TMEM173) plays an essential role in DNA virus‐ or cytosolic DNA‐triggered innate immune responses. Here, we demonstrate that the RING‐in‐between RING (RBR) E3 ubiquitin ligase family member RING‐finger protein (RNF) 144A interacts with STING and promotes its K6‐linked ubiquitination at K236, thereby enhancing STING translocation from the ER to the Golgi and downstream signaling pathways. The K236R mutant of STING displays reduced activity in promoting innate immune signal transduction. Overexpression of RNF144A upregulates HSV‐1‐ or cytosolic DNA‐induced immune responses, while knockdown of RNF144A expression has the opposite effect. In addition, Rnf144a‐deficient cells exhibit impaired DNA virus‐ or cytosolic DNA‐triggered signaling, and RNF144A protects mice from DNA virus infection. In contrast, RNF144A does not affect RNA virus‐ or cytosolic RNA‐triggered innate immune responses. Taken together, our findings identify a new positive regulator of DNA virus‐ or cytosolic DNA‐triggered signaling pathways and a critical ubiquitination site important for fully functional STING during antiviral responses.