Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling

Cell. 2013 Oct 24;155(3):688-98. doi: 10.1016/j.cell.2013.09.049. Epub 2013 Oct 10.

Abstract

Activation of the stimulator of interferon genes (STING) pathway by microbial or self-DNA, as well as cyclic dinucleotides (CDNs), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent proinflammatory disease by mechanisms that remain unknown. We demonstrate here that, after autophagy-dependent STING delivery of TANK-binding kinase 1 (TBK1) to endosomal/lysosomal compartments and activation of transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1), and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor AMP activated protein kinase (AMPK) and was elicited by CDNs generated by the cGAMP synthase, cGAS. Thus, although CDNs may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Autophagy-Related Protein-1 Homolog
  • Humans
  • Immunity, Innate*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Nucleotides, Cyclic / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sequence Alignment
  • Signal Transduction*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nucleotides, Cyclic
  • STING1 protein, human
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human
  • Ulk2 protein, human

Associated data

  • GEO/GSE51199