The STING phase-separator suppresses innate immune signalling

Yu, Xiaoyu; Zhang, Liyuan; Shen, Jingxiang; Zhai, Yanfang; Jiang, Qifei; Yi, Mengran; Deng, Xiaobing; Ruan, Ziran; Fang, Run; Chen, Zhaolong; Ning, Xiaohan; Jiang, Zhengfan

doi:10.1038/s41556-021-00659-0

Cited by 126 publications

(96 citation statements)

References 67 publications

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“…A recent study showed that STING can condensate into puzzle-like structures in the ER via liquid-liquid phase separation of soluble proteins. These biomolecular condensates limit the immune response to pathogen invasion by sequestering STING and TBK1 [75]. Formation of biomolecular condensates was dependent on cGAMP levels suggesting a level of feedback regulation to prevent pathway overactivation.…”

Section: Mechanism Of Cgas Controlmentioning

confidence: 99%

Sensing Stemness

Bowman

Trompouki

2021

Curr Stem Cell Rep

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Purpose of Review Hematopoietic stem cells (HSCs) are formed embryonically during a dynamic developmental process and later reside in adult hematopoietic organs in a quiescent state. In response to their changing environment, HSCs have evolved diverse mechanisms to cope with intrinsic and extrinsic challenges. This review intends to discuss how HSCs and other stem cells co-opted DNA and RNA innate immune pathways to fine-tune developmental processes. Recent Findings Innate immune receptors for nucleic acids like the RIG-I-like family receptors and members of DNA sensing pathways are expressed in HSCs and other stem cells. Even though the “classic” role of these receptors is recognition of foreign DNA or RNA from pathogens, it was recently shown that cellular transposable element (TE) RNA or R-loops activate such receptors, serving as endogenous triggers of inflammatory signaling that can shape HSC formation during development and regeneration. Summary Endogenous TEs and R-loops activate RNA and DNA sensors, which trigger distinct inflammatory signals to fine-tune stem cell decisions. This phenomenon could have broad implications for diverse somatic stem cells, for a variety of diseases and during aging.

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Section: Mechanism Of Cgas Controlmentioning

confidence: 99%

Sensing Stemness

Bowman

Trompouki

2021

Curr Stem Cell Rep

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“…Another important N-terminal domain in cGAS is responsible for maintaining the liquid phase of dsDNA and cGAS. The non-specific ion interaction between the positively charged N-terminal of cGAS and the structural contact between the C site and dsDNA enforce cGAS/DNA liquid-liquid phase separation (LLPS) ( 7 ), which is beneficial for dimerization and protects DNA from the degradation of three-prime repair exonuclease 1 (TREX1) to promote cGAS activity ( 8 ).…”

Section: Overview Of the Cgas/sting Pathwaymentioning

confidence: 99%

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Gan

Han

et al. 2022

Front. Immunol.

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As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

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“…In contrast, a phase separation-deficient but catalytic domain-intact cGAS mutant requires much higher DNA concentrations to initiate its activity (Du and Chen, 2018). cGAS condensates thus promote non-linear signal amplification (Brandman and Meyer, 2008), yielding a switch-like response consistent with the sensitive detection of cytosolic dsDNA (Yu et al, 2021b;Zhou et al, 2021). Overall, LLPS regulates cGAS function through compartmentation and creates a biochemical environment that favors DNA-induced activation of cGAS.…”

Section: Mechanistic Principles Of Signaling Condensates: the Cgas-sting Pathwaymentioning

confidence: 99%

“…In addition, as TREX1 diffuses slowly into the cGAS core, the biochemical environment within the core condensate further suppresses enzymatic activity of TREX1 (Zhou et al, 2021). Recently, STING was also reported to form biomolecular condensates on the ER membrane, triggered by cGAMP binding and mediated by its IDR and dimerization domain (Yu et al, 2021b). STING condensates were shown to compartmentalize both its negative regulator TANK binding protein 1 and its activator cGAMP, thereby buffering cGAMP concentrations to modulate immune signaling strength (Yu et al, 2021b).…”

Section: Mechanistic Principles Of Signaling Condensates: the Cgas-sting Pathwaymentioning

confidence: 99%

Liquid-liquid phase separation: Orchestrating cell signaling through time and space

2021

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Cell signaling is a complex process. The faithful transduction of information into specific cellular actions depends on the synergistic effects of many regulatory molecules, nurtured by their strict spatiotemporal regulation. Over the years, we have gained copious insights into the subcellular architecture supporting this spatiotemporal control, including the roles of membrane-bound organelles and various signaling nanodomains. Recently, liquid-liquid phase separation (LLPS) has been recognized as another potentially ubiquitous framework for organizing signaling molecules with high specificity and precise spatiotemporal control in cells. Here, we review the pervasive role of LLPS in signal transduction, highlighting several key pathways that intersect with LLPS, including examples in which LLPS is controlled by signaling events. We also examine how LLPS orchestrates signaling by compartmentalizing signaling molecules, amplifying signals non-linearly, and moderating signaling dynamics. We focus on the specific molecules that drive LLPS and highlight the known functional and pathological consequences of LLPS in each pathway.

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The STING phase-separator suppresses innate immune signalling

Cited by 126 publications

References 67 publications

Sensing Stemness

Sensing Stemness

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Liquid-liquid phase separation: Orchestrating cell signaling through time and space

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