Clathrin-associated AP-1 controls termination of STING signalling.
Clathrin-associated AP-1 controls termination of STING signalling.
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DOI：
10.1038/s41586-022-05354-0
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发表时间：
2022-10
期刊：
影响因子：
64.8
通讯作者：
Ablasser, Andrea
中科院分区：
文献类型：
--
作者：
Liu, Ying;Xu, Pengbiao;Rivara, Sophie;Liu, Chong;Ricci, Jonathan;Ren, Xuefeng;Hurley, James H.;Ablasser, Andrea
干扰素基因刺激因子（STING）在DNA传感中在环状GMP-AMP合酶下游起作用，或作为细菌环状二核苷酸和小分子的直接受体，以在感染、癌症和免疫治疗期间激活免疫。STING的精确调节对于确保平衡的免疫反应和预防有害的自身炎症至关重要。活化后，STING（一种跨膜蛋白）从内质网运输到高尔基体，在高尔基体中其被蛋白激酶TBK 1磷酸化，从而实现信号转导。在高尔基体终止STING信号的机制仍然未知。在这里，我们表明衔接蛋白复合物1（AP-1）控制STING依赖性免疫激活的终止。我们发现AP-1将磷酸化的STING分类到网格蛋白包被的运输囊泡中，用于递送到内溶酶体系统，在那里STING被降解。我们在STING的胞质C-末端尾（CTT）中鉴定了高度保守的双亮氨酸基序，其与TBK 1依赖性CTT磷酸化一起决定了STING的AP-1接合。AP-1与磷酸化STING复合的冷冻电子显微镜结构解释了TBK 1激活的STING的增强识别。我们发现AP-1的抑制加剧了STING诱导的免疫反应。我们的研究结果揭示了STING负调控的结构机制，并确定信号传导的启动与其终止密不可分，以实现免疫的瞬时激活。衔接蛋白AP-1通过一种机制控制STING信号传导的关闭，在该机制中AP-1识别磷酸化STING中的双亮氨酸基序，这导致STING靶向转运至内溶酶体系统进行降解。
Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate immunity during infection, cancer and immunotherapy. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction. The mechanism that ends STING signalling at the Golgi remains unknown. Here we show that adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation. We find that AP-1 sorts phosphorylated STING into clathrin-coated transport vesicles for delivery to the endolysosomal system, where STING is degraded. We identify a highly conserved dileucine motif in the cytosolic C-terminal tail (CTT) of STING that, together with TBK1-dependent CTT phosphorylation, dictates the AP-1 engagement of STING. A cryo-electron microscopy structure of AP-1 in complex with phosphorylated STING explains the enhanced recognition of TBK1-activated STING. We show that suppression of AP-1 exacerbates STING-induced immune responses. Our results reveal a structural mechanism of negative regulation of STING and establish that the initiation of signalling is inextricably associated with its termination to enable transient activation of immunity. The adaptor protein AP-1 controls the shutdown of STING signalling through a mechanism in which AP-1 recognizes a dileucine motif in phosphorylated STING, which leads to targeted transport of STING to the endolysosomal system for degradation.
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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：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
3.3
作者：
Doray, Balraj;Lee, Intaek;Kornfeld, Stuart
通讯作者：
Kornfeld, Stuart
影响因子：
15.9
作者：
Jeremiah, Nadia;Neven, Benedicte;Rieux-Laucat, Frederic
通讯作者：
Rieux-Laucat, Frederic