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

Hertzog, Jonny; Zhou, Wen; Fowler, Gerissa; Rigby, Rachel E.; Bridgeman, Anne; Blest, Henry TW; Cursi, Chiara; Chauveau, Lise; Davenne, Tamara; Warner, Benjamin E.; Kinchington, Paul R.; Kranzusch, Philip J.; Rehwinkel, Jan

doi:10.15252/embj.2021109217

Cited by 33 publications

(25 citation statements)

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“…Understanding other potential SARS-CoV-2 sensors/receptors may help to offer new insights and identify potential therapeutic targets to develop better treatment options for COVID-19 (41)(42)(43). cGAS is a key DNA sensor that activates STING1 to cause type I IFN production (13)(14)(15)(16)(17)(18), and the varicella-zoster virus ORF9 exerts an antagonistic effect on the cGAS DNA sensor (44). As a result, cGAS is a key factor in COVID-19 infection and progression, and it may be a potential new target for effective COVID-19 treatment.…”

Section: Discussionmentioning

confidence: 99%

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Chen¹,

Xian²,

Wang³

et al. 2023

Ann Transl Med

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Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase ( cGAS ) could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on cGAS gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of cGAS in malignant tumors. Methods cGAS expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate cGAS expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes. Results Compared to normal tissues, cGAS was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). cGAS expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of cGAS genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with cGAS expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in cGAS expression in vitro . Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. According to the evidence presented above, cGAS may become an important target for cancer therapy. Conclusions This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS , making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diag...

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Section: Discussionmentioning

confidence: 99%

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Chen¹,

Xian²,

Wang³

et al. 2023

Ann Transl Med

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“…On the other hand, one study identi ed an important role of STING in mounting type I and Type III IFN responses to VZV in human dermal broblasts and HaCaT keratinocytes with potential implications for varicella pathogenesis and suggesting an important role of cGAS-STING in the skin [49]. Recently, the cGAS-STING DNA sensing pathway was demonstrated to be required for IFN induction and VZV restriction during VZV infection in THP1 cells and the VZV protein ORF9 was reported to antagonize cGAS-STING signaling and IFN production [50]. The observation that POL III dominates as VZV sensor in mononuclear cells might in fact explain why we do not observe signi cantly decreased IFN induction in PBMCs in response to VZV, and only could measure a modest increased in VZV replication in this cell type from the patient.…”

Section: Discussionmentioning

confidence: 99%

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Thomsen¹,

Heinz²,

Hollensen³

et al. 2022

Preprint

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Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, where it causes two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy. Here we describe a 3-year-old boy with severe VZV infection involving the central nervous system, subsequently triggering longstanding hemophagocytic lymphohistiocytosis (HLH). We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor AMFR encoding an ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase – stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response to the cGAS agonists 2’3’-cGAMP and dsDNA, as well as decreased IFN induction in response to herpes virus. VZV replication in patient PBMCs was found to be slightly increased compared to healthy controls. Overexpression of the variant AMFR p.R594C resulted in decreased K27-linked STING ubiquitination compared to expression of WT AMFR. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in control of viral infections in humans.

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“…The cGAS-STING pathway plays an essential role in host defensing against various DNA viruses, while virus explores series of immune evasion strategies against the sensing ( 31 ). It has been reported that virus-derived ORF 52, VP22 ( 32 ), KicGAS ( 30 ) and ORF9 ( 33 ) can extract DNA molecules from cGAS-DNA droplets and bind to itself to form new droplets, which leads to the dispersion of cGAS-DNA droplets or reduces the DNA-mediated liquid phase separation of cGAS-DNA, thereby alleviating the cGAS-STING pathway and resulting in immune dysregulation ( 31 ) ( Figure 1D ).…”

Section: Cgas-dna Phase Separation Enhances Innate Immune Responses T...mentioning

confidence: 99%

Phase separation in innate immune response and inflammation-related diseases

Liu

et al. 2023

Front. Immunol.

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Inflammation induced by nonspecific pathogenic or endogenous danger signals is an essential mechanism of innate immune response. The innate immune responses are rapidly triggered by conserved germline-encoded receptors that recognize broad patterns indicative of danger, with subsequent signal amplification by modular effectors, which have been the subject of intense investigation for many years. Until recently, however, the critical role of intrinsic disorder-driven phase separation in facilitating innate immune responses went largely unappreciated. In this review, we discuss emerging evidences that many innate immune receptors, effectors, and/or interactors function as “all-or-nothing” switch-like hubs to stimulate acute and chronic inflammation. By concentrating or relegating modular signaling components to phase-separated compartments, cells construct flexible and spatiotemporal distributions of key signaling events to ensure rapid and effective immune responses to a myriad of potentially harmful stimuli.

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

Cited by 33 publications

References 100 publications

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Phase separation in innate immune response and inflammation-related diseases

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