The STING phase-separator suppresses innate immune signalling

Biomolecular condensates (biocondensates) formed via liquid–liquid phase-separation of soluble proteins have been studied extensively. However, neither the phase-separation of endoplasmic reticulum (ER) transmembrane protein nor a biocondensate with organized membranous structures has been reported....

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Published in:	Nature cell biology Vol. 23; no. 4; pp. 330 - 340
Main Authors:	Yu, Xiaoyu, Zhang, Liyuan, Shen, Jingxiang, Zhai, Yanfang, Jiang, Qifei, Yi, Mengran, Deng, Xiaobing, Ruan, Ziran, Fang, Run, Chen, Zhaolong, Ning, Xiaohan, Jiang, Zhengfan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2021 Nature Publishing Group
Subjects:	101/58 14/19 14/28 14/34 14/35 38/109 38/70 631/250/262 631/80/86 82/80 82/83 96/1 96/21 96/44 96/95 AMP Biomedical and Life Sciences Biomolecules Cancer Research Cell activation Cell Biology Condensates Condensation Cyclic GMP Deoxyribonucleic acid Development and progression Developmental Biology Dimerization DNA DNA viruses Domains Endoplasmic reticulum Endoplasmic Reticulum - genetics Genetic aspects Health aspects Humans Immune response Immunity Immunity, Innate - genetics Innate immunity Interferon Life Sciences Liquid phases Liquid-Liquid Extraction Membrane proteins Membrane Proteins - genetics Nucleotides, Cyclic - genetics Phase transformations (Statistical physics) Protein Binding - genetics Protein Serine-Threonine Kinases - genetics Proteins Separation Separators Signal Transduction - genetics Stem Cells Stimulators Structure Translocation Transmembrane domains Virus diseases Viruses China
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Summary:	Biomolecular condensates (biocondensates) formed via liquid–liquid phase-separation of soluble proteins have been studied extensively. However, neither the phase-separation of endoplasmic reticulum (ER) transmembrane protein nor a biocondensate with organized membranous structures has been reported. Here, we have discovered a spherical ER membranous biocondensate with puzzle-like structures caused by condensation of the ER-resident stimulator of interferon genes (STING) in DNA virus-infected or 2′3′-cGAMP (cyclic GMP-AMP)-treated cells, which required STING transmembrane domains, an intrinsically disordered region (IDR) and a dimerization domain. Intracellular 2′3′-cGAMP concentrations determined STING translocation or condensation. STING biocondensates constrained STING and TBK1 (TANK binding protein 1) to prevent innate immunity from overactivation, presumably acting like a ‘STING-TBK1-cGAMP sponge’. Cells expressing STING-E 336 G/E 337 G showed notably enhanced innate immune responses due to impaired STING condensation after viral infection at later stages. Microtubule inhibitors impeded the STING condensate gel-like transition and augmented type I-interferon production in DNA virus-infected cells. This membranous biocondensate was therefore named the STING phase-separator. Yu et al. identify that STING bicondensates occur in virus-infected cells, thereby restricting TBK1 activation and innate immunity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-7392 1476-4679
DOI:	10.1038/s41556-021-00659-0