<scp>HSV</scp>
            ‐1
            <scp>ICP</scp>
            27 targets the
            <scp>TBK</scp>
            1‐activated STING signalsome to inhibit virus‐induced type I
            <scp>IFN</scp>
             expression

Christensen, Maria H; Jensen, Søren Astrup; Miettinen, Juho J.; Luecke, Stefanie; Prabakaran, Thaneas; Reinert, Line S.; Mettenleiter, Thomas C.; Chen, Zhijian J.; Knipe, David M.; Sandri‐Goldin, Rozanne M.; Enquist, Lynn W.; Hartmann, Rune; Mogensen, Trine H.; Rice, Stephen A.; Nyman, Tuula A.; Matikainen, Sampsa; Paludan, Søren R.

doi:10.15252/embj.201593458

Cited by 185 publications

(114 citation statements)

References 63 publications

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“…Our previous study has demonstrated that VP24 inhibited the cGAS-STING-mediated IFN-␤ signaling pathway by blocking the interaction between TBK1 and IRF3 (37). In addition, a recent study by Christensen et al demonstrated that HSV-1 immediate early protein ICP27 interacted with TBK1 and STING and abrogated activation of IRF3 (38). Nevertheless, our current knowledge on the countermeasure of DNA viruses against the cGAS/STING-mediated DNA-sensing signal pathway is still limited, and no viral protein has been identified to act directly on cGAS.…”

Section: Discussionmentioning

confidence: 95%

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Zheng

2017

J Virol

141

106

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Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STINGmediated IFN-␤ promoter activation and IFN-␤ production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/ STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.KEYWORDS HSV-1, vhs/UL41, cGAS, DNA sensing T he innate immune system is the first line of defense against invading pathogens and is crucial for the subsequent activation of the adaptive immune response. The first step in innate immunity is to detect the invading pathogen through various pathogen recognition receptors (PRRs) which recognize pathogen-associated molecular patterns and trigger the production of type I interferon (IFN) and other antiviral factors (1, 2). Besides Toll-like receptors in the cellular membrane or endosome, Nod-like receptors and the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) in the cytoplasm, there are also several recently discovered cytosolic DNA sensors, such as cyclic GMP-AMP (cGAMP) synthase (cGAS), gamma interferon-inducible protein 16

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Section: Discussionmentioning

confidence: 95%

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Zheng

2017

J Virol

141

106

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“…In this setting, the viral interferon-regulatory factor (vIRF1) of Kaposi’s sarcoma-associated herpesvirus (KSHV) inhibits STING phosphorylation and concomitant activation by preventing its interaction with TBK1 [28]. In addition, ICP27, a regulatory protein encoded by herpes simplex virus type 1, prevents the phosphorylation of IRF3 by interacting with STING and TBK1 [29]. Likewise, HPV E7 and Adenovirus E1A binds STING through a LXCXE motif and antagonizes DNA sensing in vitro [7], while E2 proteins of high risk HPV can also reduce STING expression and IFN-κ transcription in human keratinocytes [20].…”

Section: Discussionmentioning

confidence: 99%

STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Concha-Benavente

Shayan

et al. 2018

Oral Oncology

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Objectives The intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab. Materials and methods We correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system. Results In this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV+) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation. Conclusion Our findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor.

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“…This indicates that both the TLR3-TRIF and cGAS-STING pathways are involved in control of HSV1 infections. In further support of a role for the cGAS-STING pathway in control of HSV1, there are now reports of close to 10 HSV1-encoded proteins targeting this pathway (Christensen et al, 2016;Deschamps and Kalamvoki, 2017;Huang et al, 2018;Orzalli et al, 2012b;Su and Zheng, 2017;Verpooten et al, 2009;Wang et al, 2013b;Ye et al, 2017;Zhang et al, 2018). However, it remains unresolved how HSV1 evades the IFN-mediated immune response in the brain.…”

Section: Introductionmentioning

confidence: 99%

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection

Bodda

Reinert

Fruhwürth

et al. 2020

Journal of Experimental Medicine

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Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS–STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain.

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HSV ‐1 ICP 27 targets the TBK 1‐activated STING signalsome to inhibit virus‐induced type I IFN expression

Cited by 185 publications

References 63 publications

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection

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