UNC13D inhibits STING signaling by attenuating its oligomerization on the endoplasmic reticulum
UNC13D inhibits STING signaling by attenuating its oligomerization on the endoplasmic reticulum
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UNC13D 通过减弱内质网寡聚化来抑制 STING 信号传导
DOI：
10.15252/embr.202255099
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发表时间：
2022-09
期刊：
影响因子：
7.7
通讯作者：
Danying Chen
中科院分区：
文献类型：
--
作者：
Pu Song;Weiwei Yang;Karen F Lou;Hao Dong;Heng Zhang;Beiming Wang;Danying Chen
干扰素基因刺激因子（STING）是位于内质网（ER）上的必需信号蛋白，并且响应于致病DNA而触发I型干扰素（IFN）和促炎细胞因子的产生。STING的异常激活与自身免疫性疾病有关。STING的稳态调节机制尚不清楚。在这里，我们报告了与家族性噬血细胞性淋巴组织细胞增多症（FHL 3）相关的UNC 13 D是STING介导的先天免疫应答的负调节因子。UNC 13 D与ER上的STING共定位并抑制STING寡聚化。细胞敲除和UNC 13 D敲除促进DNA病毒诱导的干扰素-β（IFN-β）的产生，但不促进RNA病毒。此外，UNC 13 D缺乏还增加了促炎细胞因子的基础水平。这些作用被STING信号传导的抑制剂减弱。此外，还绘制了两种蛋白质上涉及UNC 13 D/STING相互作用的结构域。我们的研究结果提供了深入了解STING的调控机制，UNC 13 D以前未知的细胞功能和FHL 3的潜在发病机制。
Stimulator of interferon genes (STING) is an essential signaling protein that is located on the endoplasmic reticulum (ER) and triggers the production of type I interferons (IFN) and proinflammatory cytokines in response to pathogenic DNA. Aberrant activation of STING is linked to autoimmune diseases. The mechanisms underlying homeostatic regulation of STING are unclear. Here, we report that UNC13D, which is associated with familial hemophagocytic lymphohistiocytosis (FHL3), is a negative regulator of the STING‐mediated innate immune response. UNC13D colocalizes with STING on the ER and inhibits STING oligomerization. Cellular knockdown and knockout of UNC13D promote the production of interferon‐β (IFN‐β) induced by DNA viruses, but not RNA viruses. Moreover, UNC13D deficiency also increases the basal level of proinflammatory cytokines. These effects are diminished by an inhibitor of STING signaling. Furthermore, the domains involved in the UNC13D/STING interaction on both proteins are mapped. Our findings provide insight into the regulatory mechanism of STING, the previously unknown cellular function of UNC13D and the potential pathogenesis of FHL3.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
64.8
作者：
Chu TT;Tu X;Yang K;Wu J;Repa JJ;Yan N
通讯作者：
Yan N
影响因子：
20.3
作者：
Meeths, Marie;Chiang, Samuel C. C.;Bryceson, Yenan T.
通讯作者：
Bryceson, Yenan T.
影响因子：
64.5
作者：
S. L. Ergun;D. Fernández;T. Weiss;Lingyin Li
通讯作者：
S. L. Ergun;D. Fernández;T. Weiss;Lingyin Li
影响因子：
20.3
作者：
Jan-lnge Henter;G. Elinder;Olle Soder;Mona Hansson;Birger Andersson;U. Andersson
通讯作者：
Jan-lnge Henter;G. Elinder;Olle Soder;Mona Hansson;Birger Andersson;U. Andersson