DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway

Lau, Laura; Gray, Elizabeth; Brunette, Rebecca; Stetson, Daniel B.

doi:10.1126/science.aab3291

Cited by 385 publications

(371 citation statements)

References 54 publications

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“…Human foreskin fibroblasts (HFFs) express many DNA sensors, including cGAS, and have been used to study their functions (15,22). Immunostimulatory DNA (ISD) is a double-stranded DNA 60-mer oligonucleotide derived from the HSV-1 genome and has a high capacity to induce IFN-␤ production (23).…”

Section: Resultsmentioning

confidence: 99%

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

Zheng

2017

J Virol

143

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: Resultsmentioning

confidence: 99%

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

Zheng

2017

J Virol

143

106

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“…This discrepancy likely explains that is shared by other tumor cell types (54). E7 and E1A oncoproteins expressed by the human papillomavirus (HPV) and adenoviruses, respectively, potently inhibit the cGAS-STING pathway by binding STING and blocking its activation (35). Thus, inhibition of STING pathway activation may represent a mechanism of immune evasion during carcinogenesis.…”

Section: Sting Pathway Activation In Other Cell Typesmentioning

confidence: 99%

“…Indeed, most immortalized and tumor cell lines, but not primary cells, fail to generate type I IFNs in response to intracellular DNA (34). One of the molecular mechanisms that may explain this observation is that certain oncoproteins antagonize innate immune signaling that leads to the transcription of type I IFNs and other immune cytokines (35,36). Another mechanism that has been observed in both leukemia and glioma cells is the homozygous deletion of type I IFN genes (37,38).…”

Section: Type I Ifns In the Generation Of Antitumor Immune Responsesmentioning

confidence: 99%

The host STING pathway at the interface of cancer and immunity

Corrales¹,

McWhirter²,

Dubensky³

et al. 2016

Journal of Clinical Investigation

368

305

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“…To confirm that the mRNA and surface expression of ISG molecules reflected bioactive interferon in the spleen, we utilized an L929 cell line that stably expresses luciferase under a type I IFN-specific promoter (25). Coculture of splenocytes taken from mice at day 7 after infection revealed an elevated luciferase signal in WT mice compared with cGAS -/-mice ( Figure 2C).…”

Section: Cd11bmentioning

confidence: 99%