Clathrin-associated AP-1 controls termination of STING signalling

  • Nature. 2022 Oct 19. doi: 10.1038/s41586-022-05354-0.
Ying Liu  #  1 ,  Pengbiao Xu  #  1 ,  Sophie Rivara  #  1 ,  Chong Liu  1 ,  Jonathan Ricci  1 ,  Xuefeng Ren  2 ,  James H Hurley  2  3 ,  Andrea Ablasser  4
Affiliations
  • 1. Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 2. Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
  • 3. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 4. Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. [email protected].
  • # Contributed equally.
PMID: 36261523 DOI: 10.1038/s41586-022-05354-0
Abstract

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.

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