Liu, YingXu, PengbiaoRivara, SophieLiu, ChongRicci, JonathanRen, XuefengHurley, James H.Ablasser, Andrea2022-11-212022-11-212022-11-212022-10-1910.1038/s41586-022-05354-0https://infoscience.epfl.ch/handle/20.500.14299/192393WOS:000870207100003Stimulator 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(1-10). Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation(11-16). 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(17-20). 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(21). 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.Multidisciplinary SciencesScience & Technology - Other Topicscyclic gmp-ampstructural basis2nd-messengeradapteractivationdinucleotiderecruitmentbindingsensormicetext::journal::journal article::research article