title: DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway.
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.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Lau
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gray
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Brunette
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. stetson@uw.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stetson
mesh_terms: D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D004263:DNA Tumor Viruses / Q000276:immunology*; D004273:DNA, Neoplasm / Q000276:immunology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D009712:Nucleotides, Cyclic / Q000037:antagonists & inhibitors*; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors; D019139:Tumor Escape; D000099197:STING Protein
chemical_list: D017500:Adenovirus E1A Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; C052633:E7 protein, Human papillomavirus type 18; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate