Activation of STING requires palmitoylation at the Golgi

Nat Commun. 2016 Jun 21;7:11932. doi: 10.1038/ncomms11932.

Abstract

Stimulator of interferon genes (STING) is essential for the type I interferon response against DNA pathogens. In response to the presence of DNA and/or cyclic dinucleotides, STING translocates from the endoplasmic reticulum to perinuclear compartments. However, the role of this subcellular translocation remains poorly defined. Here we show that palmitoylation of STING at the Golgi is essential for activation of STING. Treatment with palmitoylation inhibitor 2-bromopalmitate (2-BP) suppresses palmitoylation of STING and abolishes the type I interferon response. Mutation of two membrane-proximal Cys residues (Cys88/91) suppresses palmitoylation, and this STING mutant cannot induce STING-dependent host defense genes. STING variants that constitutively induce the type I interferon response were found in patients with autoimmune diseases. The response elicited by these STING variants is effectively inhibited by 2-BP or an introduction of Cys88/91Ser mutation. Our results may lead to new treatments for cytosolic DNA-triggered autoinflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Embryo, Mammalian
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism
  • Fibroblasts / immunology*
  • Fibroblasts / virology
  • Gene Expression Regulation
  • Golgi Apparatus / immunology
  • Golgi Apparatus / metabolism*
  • HEK293 Cells
  • Herpesvirus 1, Human / growth & development
  • Herpesvirus 1, Human / immunology
  • Humans
  • Immunity, Innate*
  • Interferon Type I / genetics*
  • Interferon Type I / immunology
  • Lipoylation
  • Membrane Proteins / agonists
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Mutation
  • Palmitates / pharmacology
  • Primary Cell Culture
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Xanthones / pharmacology

Substances

  • Interferon Type I
  • Membrane Proteins
  • Palmitates
  • STING protein, human
  • Xanthones
  • vadimezan
  • 2-bromopalmitate
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human