MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway

Tian, Mingfu; Liu, Weiyong; Zhang, Qi; Huang, Yin; Li, Wen; Wang, Wenbiao; Zhao, Peiyi; Huang, Shanyu; Song, Yunting; Shereen, Muhammad Adnan; Qin, Mengying; Liu, Yingle; Wu, Jianguo

doi:10.1016/j.celrep.2020.108297

Cited by 59 publications

(55 citation statements)

References 48 publications

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“…STING-activated Type I IFNs are key cytokines induced by antimicrobial and antiviral immunity. In order to avoid continuous innate immune-related pro-inflammatory cytokine expression, STING is controlled by negative feedback and rapidly subjected to degradation [29,38]. This makes the STING pathway an important regulator of host defense against pathogens, in addition to its essential role in protecting the host tissues from the development of cancer [28,30].…”

Section: Intracellular Nucleic Acid Receptors In Mammalian Cells and The Sting/tbk1/irf3 Pathwaymentioning

confidence: 99%

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

et al. 2021

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Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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Section: Intracellular Nucleic Acid Receptors In Mammalian Cells and The Sting/tbk1/irf3 Pathwaymentioning

confidence: 99%

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

et al. 2021

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“…Other approaches target modifying enzymes involved in the synthesis of STING ligands and/or the posttranslational modifications of cGAS and STING (129). In addition, targeted approaches are being developed based on the modulators of the cGAS-STING pathway such as the immunosuppressor MYSM1, which may be considered as a therapeutic target for inflammatory and autoimmune diseases (130).…”

Section: Discussion and Perspectives: Cgas-sting As A Targetable Pathway In Therapymentioning

confidence: 99%

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

Verrier

Langevin

2021

Front. Immunol.

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Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.

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“…Similarly, mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and RNF115 directly interact with STING and catalyze K63-linked polyubiquitination of STING at K224 and K20, K224, K289, respectively, to promote its translocation from ER to Golgi apparatus for activations [111,112]. Conversely, cytosolic DNA stimulation induces the expression of myb-like, SWIRM, and MPN domains 1 protein (MYSM1), which interacts with STING and cleaves STING K63-linked ubiquitination at K150 to restrict STING overactivation [113]. Moreover, ER membrane protein insulin-induced gene 1 (INSIG1) bridges autocrine motility factor receptor (AMFR) and STING and promotes AMFR-catalyzed K27 polyubiquitination of STING at K137, K150, K224, and K236, which serve as an anchoring platform for recruiting TBK1 [114].…”

Section: Accepted Articlementioning

confidence: 99%

cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases

Hong

Liu

et al. 2021

The FEBS Journal

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Cytoplasmic microbial and host aberrant DNAs act as danger signals and trigger host immune responses. Upon recognition, the cytosolic DNA sensor cyclic GMP–AMP synthase (cGAS) catalyzes the production of a second messenger 2′3′‐cGAMP, which activates endoplasmic reticulum (ER)‐associated stimulator of interferon (IFN) genes (STING) and ultimately leads to the induction of type I IFNs and inflammatory genes that collectively initiate host immune defense against microbial invasion. Inappropriate activation or suppression of this signaling pathway has been implicated in the development of some autoimmune diseases, sterile inflammation, and cancers. In this review, we describe how the activity of cGAS and STING is regulated by host post‐translational modifications and summarize the recent advances of cell‐specific cGAS‐STING activation and its association in sterile inflammatory diseases. We also discuss key outstanding questions in the field, including how our knowledge of cGAS‐STING pathway could be translated into clinical applications.

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MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway

Cited by 59 publications

References 48 publications

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases

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