4.8 Article

Clathrin-associated AP-1 control stermination of STING signalling

期刊

NATURE
卷 610, 期 7933, 页码 761-+

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NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05354-0

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资金

  1. Swiss National Science Foundation [310030_188759]
  2. Dr. Josef Steiner Cancer Research Foundation
  3. European Union [804933]
  4. Leenaards Foundation
  5. Fondation Acteria
  6. US National Institutes of Health [R01 AI 120691]
  7. EMBO Postdoctoral Fellowships [ALTF 184-2021, ALTF 88-2022]
  8. Swiss National Science Foundation (SNF) [310030_188759] Funding Source: Swiss National Science Foundation (SNF)
  9. European Research Council (ERC) [804933] Funding Source: European Research Council (ERC)

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The adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation by sorting phosphorylated STING into transport vesicles for degradation.
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(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.

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