RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses.
RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses.
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RINCK 介导的 cGAS 单泛素化促进抗病毒先天免疫反应
DOI：
10.1186/s13578-018-0233-3
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发表时间：
2018
影响因子：
7.5
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Liu ZS;Zhang ZY;Cai H;Zhao M;Mao J;Dai J;Xia T;Zhang XM;Li T
作为一个重要的危险信号，细胞质中DNA的存在引发了强有力的免疫反应。环GMP-AMP合酶（cGAS）是最近鉴定的细胞质DNA的关键传感器。cGAS与DNA的接合导致第二信使环GMP-AMP（cGAMP）的合成，其结合并激活下游衔接蛋白STING以促进I型干扰素产生。虽然cGAS已被证明在先天免疫中发挥关键作用，但cGAS激活的确切调控尚未完全了解。我们报告了E3泛素连接酶，与C激酶相互作用的RING指蛋白（RINCK，也称为三重基序蛋白41，TRIM 41），通过介导cGAS的单泛素化对cGAS活化至关重要。使用CRISPR/Cas9，我们产生了RINCK缺失细胞，并表明RINCK的缺乏导致响应胞质DNA的干扰素产生减弱。同样，RINCK缺失细胞在单纯疱疹病毒1（一种DNA病毒）感染后也表现出干扰素产生不足。结果，RINCK缺陷型细胞中的病毒载量显著高于野生型细胞。我们还发现RINCK缺陷抑制了DNA触发的干扰素产生途径的上游信号传导，这通过TANK结合激酶1和干扰素调节因子3的磷酸化来反映。有趣的是，我们发现RINCK与cGAS结合并促进cGAS的单泛素化，从而正向调节cGAS介导的cGAMP合成。我们的研究表明，monoubiquitination是cGAS激活的重要调节，并揭示了RINCK在cGAS介导的先天免疫中的关键作用。
As an important danger signal, the presence of DNA in cytoplasm triggers potent immune responses. Cyclic GMP-AMP synthase (cGAS) is a recently characterized key sensor for cytoplasmic DNA. The engagement of cGAS with DNA leads to the synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which binds and activates the downstream adaptor protein STING to promote type I interferon production. Although cGAS has been shown to play a pivotal role in innate immunity, the exact regulation of cGAS activation is not fully understood. We report that an E3 ubiquitin ligase, RING finger protein that interacts with C kinase (RINCK, also known as tripartite motif protein 41, TRIM41), is critical for cGAS activation by mediating the monoubiquitination of cGAS. Using CRISPR/Cas9, we generated RINCK-deletion cells and showed that the deficiency of RINCK resulted in dampened interferon production in response to cytosolic DNA. Consistently, the RINCK-deletion cells also exhibited insufficient interferon production upon herpes simplex virus 1, a DNA virus, infection. As a result, the viral load in RINCK-deficient cells was significantly higher than that in wild-type cells. We also found that RINCK deficiency inhibited the up-stream signaling of DNA-triggered interferon production pathway, which was reflected by the phosphorylation of the TANK-binding kinase 1 and the interferon regulatory factor 3. Interestingly, we found that RINCK binds to cGAS and promotes the monoubiquitination of cGAS, thereby positively regulating the cGAS-mediated cGAMP synthesis. Our study reveals that monoubiquitination is an important regulation for cGAS activation and uncovers a critical role of RINCK in the cGAS-mediated innate immunity.
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影响因子：
8.8
作者：
Seo GJ;Yang A;Tan B;Kim S;Liang Q;Choi Y;Yuan W;Feng P;Park HS;Jung JU
通讯作者：
Jung JU
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li XD;Wu J;Gao D;Wang H;Sun L;Chen ZJ
通讯作者：
Chen ZJ
影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
Shao, Feng
DOI：
10.3109/08977194.2012.669382
发表时间：
2012-06
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Fuchs SY
通讯作者：
Fuchs SY
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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