Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway

Abstract

Beta genus human papillomaviruses ({beta}-HPVs) are ubiquitous double stranded DNA (dsDNA) viruses that may promote skin cancers by destabilizing the host genome. Supporting this, expression of the E6 gene from a {beta}-HPV ({beta}-HPV 8 E6) results in increased micronuclei that should induce an innate immune response that eliminates these cells. Yet, {beta}-HPV 8 E6 promotes rather than restricts proliferation. We hypothesize that {beta}-HPV 8 E6 accomplishes this by attenuating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, an innate immune pathway that becomes activated in response to cytosolic micronuclear dsDNA. Here, we show that in response to stimulation by transfection of pLVX-GFP plasmid, {beta}-HPV 8 E6 reduced the magnitude and intensity of cGAS-STING pathway activation in immunoblot experiments. These data also demonstrate that impairment of the cGAS-STING pathway is strongest downstream of STING phosphorylation. Further, RNA-sequencing suggests that {beta}-HPV 8 E6 downregulates other innate immune pathways. We also show that cGAS is recruited to micronuclei induced by {beta}-HPV 8 E6. These data suggest a mechanism by which {beta}-HPV 8 E6 facilitates proliferation of cells destabilized by micronuclei and support the hypothesis that the prevalence of {beta}-HPV infections is in part due to the impairment of the cGAS-STING innate immune response.