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

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Abstract

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.

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Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.

Zhijian Chen, Lijun Sun, Jiaxi Wu … (2013)

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

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Genome-scale CRISPR-Cas9 knockout screening in human cells.

Ophir Shalem, Neville Sanjana, Ella Hartenian … (2014)

The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.

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STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling

Hiroki Ishikawa, Glen N. Barber (2008)

We report here the identification, following expression cloning, of a molecule, STING (STimulator of INterferon Genes) that regulates innate immune signaling processes. STING, comprising 5 putative transmembrane (TM) regions, predominantly resides in the endoplasmic reticulum (ER) and is able to activate both NF-κB and IRF3 transcription pathways to induce type I IFN and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts (STING −/−MEFs) extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus, VSV. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpes virus family, to induce IFNβ, but did not significantly affect the Toll-like receptor (TLR pathway). Yeast-two hybrid and co-immunprecipitation studies indicated that STING interacts with RIG-I and with Ssr2/TRAPβ, a member of the translocon-associated protein (TRAP) complex required for protein translocation across the ER membrane following translation[1, 2]. RNAi ablation of TRAPβ and translocon adaptor Sec61β was subsequently found to inhibit STING’s ability to stimulate IFNβ. Thus, aside from identifying a novel regulator of innate immune signaling, this data implicates for the first time a potential role for the translocon in innate signaling pathways activated by select viruses as well as intracellular DNA.