Role of Post-Translational Modifications of cGAS in Innate Immunity

Wu, Yunqin; Li, Shitao

doi:10.3390/ijms21217842

Cited by 33 publications

(23 citation statements)

References 64 publications

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“…Various post-translational modifications of cGAS have been reported, including ubiquitination, phosphorylation, acetylation, sumoylation, glutamylation, neddylation, and caspase-mediated cleavage (Song et al, 2020;Wu and Li, 2020). For example, RNF185, a RING domain E3 ubiquitin ligase, has been shown to interact with cGAS during human simplex virus-1 (HSV-1) infection, stimulating K27-linked poly-ubiquitination of cGAS, important for cGAS enzymatic activity .…”

Section: Discussionmentioning

confidence: 99%

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Yang

Wang

Dai

et al. 2021

Preprint

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The DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is largely unknown. In this study, we screened 82 vaccinia viral genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS that elicits proteasome-dependent cGAS degradation. E5 localizes to the cytoplasm and nuclei of infected cells. Cytosolic E5 triggers K48-linked ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. E5 itself also undergoes ubiquitination and degradation. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, thereby improving the immunogenicity of the viral vector.

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Section: Discussionmentioning

confidence: 99%

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Yang

Wang

Dai

et al. 2021

Preprint

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“…The DNA fragment bound to cGAS is processed by cGAS synthetase activity to generate the second messenger cyclic GMP-AMP (cGAMP) that then binds to STING. cGAS stability and synthetase activity are balanced by ubiquitination, which is mediated by an increasing pool of E3 ligases including TRAF6, RNF185, and several TRIMs [ 166 ]. K48-linked ubiquitination of cGAS at K414 is targeted for degradation by p62-mediated selective autophagy [ 167 ].…”

Section: Trims In Regulating Prr Signaling Pathways To Ifn-i Produmentioning

confidence: 99%

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Ning

2021

Viruses

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The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

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“…cGAS was originally proposed to discriminate viral from self-DNA by cytoplasmic localization of viral DNA (Sun et al, 2013). Additional regulatory mechanisms have now been identified, which include cGAS inhibition by nucleosomes and BANF1 as well as post-translation modifications (Guey et al, 2020; Kujirai et al, 2020; Pathare et al, 2020; Wu and Li, 2020). cGAMP can move between cells to activate STING in a paracrine manner in cell culture (Ablasser et al, 2013) and in tumors (Marcus et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Bridges, not Micronuclei, Activate cGAS after Drug-induced Mitotic Errors in Human Cells

Flynn¹,

Koch

Mitchison³

2021

Preprint

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Mitotic errors can activate cGAS and induce type-I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of anti-mitotic drugs to perturb mitosis in fibroblasts and measured abnormal nuclear morphologies, cGAS localization and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of cGAMP to fibroblasts. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and anti-tumor actions of taxanes and MPS1 inhibitors, may depend on this effect.

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Role of Post-Translational Modifications of cGAS in Innate Immunity

Cited by 33 publications

References 64 publications

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Chromatin Bridges, not Micronuclei, Activate cGAS after Drug-induced Mitotic Errors in Human Cells

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