Golgi apparatus-synthesized sulfated glycosaminoglycans mediate polymerization and activation of the cGAMP sensor STING

Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identifi...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2021-05, Vol.54 (5), p.962-975.e8
Main Authors:	Fang, Run, Jiang, Qifei, Guan, Yukun, Gao, Pengfei, Zhang, Rui, Zhao, Zhen, Jiang, Zhengfan
Format:	Article
Language:	eng
Subjects:	AMP anti-viral innate immunity Apoptosis Biosynthesis Cell activation cGAS-STING CRISPR Cyclic GMP Cytokines Endoplasmic reticulum Enzymes Gag protein Genes Genomes Glycosaminoglycans Golgi apparatus Kinases Mutation Phosphorylation Polymerization Proteins Residues STING-associated vasculopathy with onset in infancy (SAVI) sulfated glycosaminoglycans (sGAGs) Sulfation Translocation Tumor necrosis factor-TNF Viruses
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Summary:	Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O-linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation. [Display omitted] •A genome-wide CRISPR-Cas9 screen identifies sGAGs for STING activation•sGAGs induce STING and TBK1 polymerization and activation•STING binds sGAGs through luminal, positively charged, and polar residues•sGAG-driven STING polymerization and activation is evolutionally conserved STING translocation from the endoplasmic reticulum to the Golgi apparatus is required for its activation. Fang et al. demonstrate that Golgi apparatus-synthesized sulfated glycosaminoglycans (sGAGs) interact with STING to initiate its oligomerization at the Golgi apparatus, thus identifying sGAGs as necessary coligands for STING activation and downstream IFN signaling.
ISSN:	1074-7613 1097-4180