Homeostatic regulation of STING by retrograde membrane traffic to the ER.
Homeostatic regulation of STING by retrograde membrane traffic to the ER.
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DOI：
10.1038/s41467-020-20234-9
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发表时间：
2021-01-04
影响因子：
16.6
通讯作者：
Taguchi T
中科院分区：
文献类型：
--
作者：
Mukai K;Ogawa E;Uematsu R;Kuchitsu Y;Kiku F;Uemura T;Waguri S;Suzuki T;Dohmae N;Arai H;Shum AK;Taguchi T
外壳蛋白复合体I(CoP-I)介导高尔基体向内质网(ER)的逆行转运。COPA基因的突变，编码COP-I亚基之一(α-COP)，会导致一种称为COPA综合征的免疫调节失调疾病。逆行转运受损导致自身炎症的分子机制仍然知之甚少。在此，我们报道了一种天然免疫蛋白--STING，它是逆行膜运输的货物。在存在致病的α-COP变异体的情况下，刺不能从高尔基体带回急诊室。STING的被迫高尔基滞留导致STING下游信号通路的cGAS非依赖和棕榈酰化依赖的激活。Surf4是一种在内质网/内质网-高尔基体中间区/高尔基体之间循环的蛋白质，它结合了STING和α-COP，并介导了STING向内质网的逆行运输。当存在致病的α-COP变异体时，STING/Surf4/α-COP复合体被破坏。我们还发现，STING配体cGAMP阻碍了STING/Surf4/α-COP复合体的形成。我们的结果提示，静息状态下的刺痛可以通过逆行膜运输进行动态平衡调节，这为COPA综合征的发病机制提供了新的见解。COPA调节高尔基体到内质网的运输，突变通过鲜为人知的机制导致自体炎症和疾病。在这里，作者证明了致病的COPA变体阻止了刺从高尔基体到内质网的运输，导致了刺通路的cGAS非依赖性激活。
Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome. COPA regulates Golgi to ER transport, and mutations lead to autoinflammation and disease through poorly understood mechanisms. Here, the authors show that disease-causing COPA variants prevent STING transport from the Golgi to the ER, leading to cGAS-independent activation of the STING pathway.
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DOI：
10.1073/pnas.1806239115
发表时间：
2018-08-14
影响因子：
11.1
作者：
Hansen AL;Buchan GJ;Rühl M;Mukai K;Salvatore SR;Ogawa E;Andersen SD;Iversen MB;Thielke AL;Gunderstofte C;Motwani M;Møller CT;Jakobsen AS;Fitzgerald KA;Roos J;Lin R;Maier TJ;Goldbach-Mansky R;Miner CA;Qian W;Miner JJ;Rigby RE;Rehwinkel J;Jakobsen MR;Arai H;Taguchi T;Schopfer FJ;Olagnier D;Holm CK
通讯作者：
Holm CK
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：
8.6
作者：
Volpi, Stefano;Tsui, Jessica;Picco, Paolo
通讯作者：
Picco, Paolo
影响因子：
64.5
作者：
Scales, SJ;Pepperkok, R;Kreis, TE
通讯作者：
Kreis, TE
影响因子：
11.4
作者：
Eugster, A;Frigerio, G;Duden, R
通讯作者：
Duden, R