A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome.
A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome.
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DOI：
10.1084/jem.20201045
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发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Shum AK
中科院分区：
文献类型：
--
作者：
Deng Z;Chong Z;Law CS;Mukai K;Ho FO;Martinu T;Backes BJ;Eckalbar WL;Taguchi T;Shum AK
由于突变COPA导致的COPI转运缺陷导致小鼠高尔基体上STING的多聚化和I型干扰素驱动的免疫失调。STING激活的小分子抑制是治疗COPA综合征的新分子靶点。致病性COPA变异体引起免疫失调的孟德尔综合征，伴随I型干扰素信号传导升高。COPA是介导高尔基体向内质网转运的外壳蛋白复合体I（COPI）的亚基。COPA WD 40结构域的错义突变损害了ER修复靶向蛋白的结合和分选，但这如何导致疾病仍不清楚。考虑到COPA在高尔基体-内质网转运中的重要性，我们推测COPA综合征中的I型干扰素信号传导涉及STING的错误分选。我们表明，COPI运输缺陷导致配体非依赖性激活STING。此外，SURF 4是一种衔接子分子，其促进高尔基体处COPA介导的STING检索。激活的STING刺激CopaE 241 K/+小鼠中I型干扰素驱动的炎症，该炎症在STING缺陷动物中被挽救。我们的研究结果表明，COPA通过调节高尔基体的STING运输来维持免疫稳态。此外，激活的STING有助于COPA综合征的免疫失调，并可能成为治疗该疾病的新分子靶点。
A defect in COPI transport due to mutant COPA causes multimerization of STING on the Golgi and type I interferon–driven immune dysregulation in mice. Small-molecule inhibition of STING activation is a new molecular target for treating COPA syndrome. Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi–ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon–driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
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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
DOI：
10.4049/jimmunol.1203086
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Otero DC;Baker DP;David M
通讯作者：
David M
影响因子：
11.4
作者：
Eugster, A;Frigerio, G;Duden, R
通讯作者：
Duden, R
影响因子：
64.8
作者：
Huttlin EL;Bruckner RJ;Paulo JA;Cannon JR;Ting L;Baltier K;Colby G;Gebreab F;Gygi MP;Parzen H;Szpyt J;Tam S;Zarraga G;Pontano-Vaites L;Swarup S;White AE;Schweppe DK;Rad R;Erickson BK;Obar RA;Guruharsha KG;Li K;Artavanis-Tsakonas S;Gygi SP;Harper JW
通讯作者：
Harper JW
影响因子：
16.6
作者：
Mukai K;Konno H;Akiba T;Uemura T;Waguri S;Kobayashi T;Barber GN;Arai H;Taguchi T
通讯作者：
Taguchi T