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

Thesis (Ph.D.)--University of Washington, 2015-12A key aspect of antiviral immunity is the induction of type I interferons (IFN) to mediate the effective clearance of a viral infection. Cyclic GMP-AMP synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate a type I IFN-mediated antiviral response to DNA viruses. These viruses, some of which have evolved with their hosts for millions of years, have likely developed means to prevent activation of the cGAS-STING pathway, but such virus-encoded antagonists remain largely unknown. Here, we identify the viral 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 cGAS-STING pathway antagonism. We find that E1A and E7 bind to STING, and that silencing of these oncogenes in human tumor cells restores cGAS-STING pathway signaling. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes, with implications for the origins of the DNA viruses that cause cancer in humans