Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1

Thaneas Prabakaran, Chiranjeevi Bodda, Christian Krapp, Bao Cun Zhang, Maria H. Christensen, Chenglong Sun, Line Reinert, Yujia Cai, Søren B. Jensen, Morten K. Skouboe, Jens R. Nyengaard, Craig B. Thompson, Robert Jan Lebbink, Ganes C. Sen, Geert van Loo, Rikke Nielsen, Masaaki Komatsu, Lene N. Nejsum, Martin R. Jakobsen, Mads Gyrd-HansenSøren R. Paludan

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy-associated vesicles. Thus, DNA sensing induces the cGAS-STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.

Original languageEnglish (US)
Article numbere97858
JournalEMBO Journal
Volume37
Issue number8
DOIs
StatePublished - Apr 13 2018
Externally publishedYes

Keywords

  • autophagy
  • DNA sensing
  • innate immunity
  • p62/SQSTM1
  • STING

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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