Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion

Xu, Guangjun; Liu, Chong; Zhou, Sheng; Li, Quanjin; Feng, Yun; Sun, Panpan; Han, Feng; Gao, Yina; Zhu, Jingpeng; Luo, Xiaohua; Zhan, Qi; Liu, Songqin; Zhu, Shu; Deng, Hongyu; Liu, Dong; Gao, Pu

doi:10.1016/j.molcel.2021.05.002

Cited by 74 publications

(60 citation statements)

References 52 publications

(69 reference statements)

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“…It is noteworthy that these experiments were performed at ~200 mM NaCl, a salt concentration at which we did not observe cGAS displacement by ORF9. It is likely that these differences can be explained by the experimental setup, which involved simultaneous mixing of DNA, cGAS, and ORF9 in our experiments and preformed DNA-cGAS complexes with subsequent addition of ORF9 in Xu et al (2021). Other parameters such as DNA length are likely important, too.…”

Section: Discussionmentioning

confidence: 99%

Varicella‐Zoster virus ORF9 is an antagonist of the DNA sensor cGAS

et al. 2022

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Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although the infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Screening of a VZV ORF expression library identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically or virally expressed ORF9 bound to endogenous cGAS leading to reduced type I IFN responses to transfected DNA. Confocal microscopy revealed co-localisation of cGAS and ORF9. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, these results reveal the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identify a VZV immune antagonist that partially but directly interferes with DNA sensing via cGAS.

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Section: Discussionmentioning

confidence: 99%

Varicella‐Zoster virus ORF9 is an antagonist of the DNA sensor cGAS

et al. 2022

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“…VP22 of HSV-1 has previously determined its function in impeding the cGAMP synthetase activity of cGAS ( Huang et al, 2018 ). Xu G. et al (2021) further clarified that gamma- and alpha-herpes tegument proteins ORF52, VP22, and ORF9 effectively disrupt the cGAS-DNA condensation as cGAS-DNA phase separation inhibitors to countermeasure viral clearance in host cells.…”

Section: Manipulation Of Cyclic Gmp-amp Synthase-stimulator Of Interferon Genes Axis By Viral Proteinsmentioning

confidence: 99%

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

et al. 2021

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Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

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“…143 Among these viral proteins, VP22, ORF52 and other structurally similar tegument proteins have been found to compete for DNA binding and phase separation with cGAS, thereby inhibiting cGAS-DNA phase separation. 144 In contrast, the HSV-1 UL37 tegument protein inhibits cGAS through posttranslational modifications. UL37 deamidates N210 within the activation loop of human cGAS, which blocks cGAMP synthesis by impinging on the catalytic site.…”

Section: Viral Targeting Of Cgas As An Immune Evasion Strategymentioning

confidence: 99%

“…VP22 and UL37 from HSV‐1, 136,137 UL31, UL42 and UL83 from human cytomegalovirus, 138–140 and ORF52 and LANA from Kaposi's sarcoma‐associated herpesvirus, 141,142 ORF9 from varicella‐zoster virus are known examples of cGAS‐inhibiting viral proteins 143 . Among these viral proteins, VP22, ORF52 and other structurally similar tegument proteins have been found to compete for DNA binding and phase separation with cGAS, thereby inhibiting cGAS‐DNA phase separation 144 . In contrast, the HSV‐1 UL37 tegument protein inhibits cGAS through post‐translational modifications.…”

Section: Regulation Of Dna Sensing and Cgas Activation Within Cellsmentioning

confidence: 99%

Control of innate immunity by the cGAS‐STING pathway

Mosallanejad

Kagan

2022

Immunol Cell Biol

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Within the cytoplasm of mammalian cells is a protein called cyclic GMP‐AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that should not exist in healthy cells – the existence of DNA in the cytosol. Upon DNA binding, cGAS synthesizes cyclic GMP‐AMP (cGAMP), a cyclic dinucleotide that activates the endoplasmic reticulum‐localized protein stimulator of interferon genes (STING). STING‐mediated signaling culminates in host defensive responses typified by inflammatory cytokine and interferon expression, and the induction of autophagy. Studies over the past several years have established a consensus in the field of the enzymatic activities of cGAS in vitro, as it relates to DNA‐induced production of cGAMP. However, much additional work is needed to understand the regulation of cGAS functions within cells, where multiple sources of DNA can create a problem of self and non‐self discrimination. In this review, we provide an overview of how the cGAS‐STING pathway mediates innate immune responses during infection and other cellular stresses. We then highlight recent progress in the understanding of the increasingly diverse ways in which this DNA‐sensing machinery is regulated inside cells, including how cGAS remains inactive to host‐derived DNA under conditions of homeostasis.

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Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion

Cited by 74 publications

References 52 publications

Varicella‐Zoster virus ORF9 is an antagonist of the DNA sensor cGAS

Varicella‐Zoster virus ORF9 is an antagonist of the DNA sensor cGAS

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

Control of innate immunity by the cGAS‐STING pathway

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