RESUMO
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 immunotherapy1-10. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation11-16. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction17-20. 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 degraded21. 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.
Assuntos
Complexo 1 de Proteínas Adaptadoras , Clatrina , Complexo 1 de Proteínas Adaptadoras/química , Complexo 1 de Proteínas Adaptadoras/metabolismo , Complexo 1 de Proteínas Adaptadoras/ultraestrutura , Clatrina/metabolismo , Microscopia Crioeletrônica , DNA/metabolismo , Imunidade Inata , Proteínas Serina-Treonina Quinases , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Motivos de Aminoácidos , Endossomos/metabolismo , Lisossomos/metabolismo , FosforilaçãoRESUMO
Two studies published in this issue of JEM, by Lepelley et al. (https://doi.org/10.1084/jem.20200600) and Deng et al. (https://doi.org/10.1084/jem.20201045), and two additional manuscripts by Mukai et al. (https://doi.org/10.1101/2020.05.20.107664 Preprint v1) and Steiner et al. (https://doi.org/10.1101/2020.07.09.194399 Preprint v1) demonstrate that COPA syndrome-associated high interferon titers are linked to mutations in COPA preventing STING's retrieval from the Golgi back to the ER and thereby causing chronic immune activation.