Activation of STING requires palmitoylation at the Golgi

Kojiro Mukai, Hiroyasu Konno, Tatsuya Akiba, Takefumi Uemura, Satoshi Waguri, Toshihide Kobayashi, Glen N. Barber, Hiroyuki Arai () and Tomohiko Taguchi ()
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Kojiro Mukai: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Hiroyasu Konno: University of Miami School of Medicine
Tatsuya Akiba: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Takefumi Uemura: Fukushima Medical University School of Medicine, Hikarigaoka
Satoshi Waguri: Fukushima Medical University School of Medicine, Hikarigaoka
Toshihide Kobayashi: Lipid Biology Laboratory, RIKEN
Glen N. Barber: University of Miami School of Medicine
Hiroyuki Arai: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Tomohiko Taguchi: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11932

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