Activation of STING requires palmitoylation at the Golgi.
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.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Lipid Biology Laboratory, RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Kojiro
K
Mukai
Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.
Hiroyasu
H
Konno
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Tatsuya
T
Akiba
Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
Takefumi
T
Uemura
Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
Satoshi
S
Waguri
Lipid Biology Laboratory, RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Toshihide
T
Kobayashi
Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.
Glen N
GN
Barber
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Hiroyuki
H
Arai
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Tomohiko
T
Taguchi
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics* / Q000276:immunology; D054878:Lipoylation; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009154:Mutation; D010168:Palmitates / Q000494:pharmacology; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D021381:Protein Transport; D044004:Xanthones / Q000494:pharmacology; D000099197:STING Protein
D007370:Interferon Type I; D008565:Membrane Proteins; D010168:Palmitates; D017346:Protein Serine-Threonine Kinases; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C066668:vadimezan; C022776:2-bromopalmitate; C403191:TBK1 protein, human