Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway

Beta human papillomaviruses (β-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 β-HPV (β-HPV 8 E6) results in increased micronuclei that should induce an innate immune response that eliminates these cells. However, β-HPV 8 E6 promotes rather than restricts proliferation. We hypothesize that β-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 dsDNA. Here, we show that in response to dsDNA transfection, β-HPV 8 E6 reduced the intensity of cGAS-STING pathway activation via a reduction in STING phosphorylation. Additionally, our unbiased assessment found that β-HPV 8 E6 broadly downregulates innate immunity. This impairment of the cGAS-STING innate immune response could contribute to the prevalence of β-HPV infections.IMPORTANCEBeta human papillomaviruses (β-HPVs) may promote non-melanoma skin cancers in certain immunocompromised populations by destabilizing the host genome. Our group has previously documented the ability of a specific β-HPV, type 8, to promote proliferation despite antiproliferative stimuli, including mitotic errors such as anaphase bridges, micronuclei, and chromothripsis. The mechanisms β-HPV uses to overcome these challenges are not yet fully elucidated. This paper addresses one possible mechanism by proposing that β-HPVs suppress cGAS-STING signaling to promote proliferation under conditions that would typically initiate an innate immune response, resulting in apoptosis or senescence. We found that β-HPVs can impair cGAS-STING signaling at a post-translational modification level and play a role in broadly downregulating innate immune-associated genes. Similarly, alpha human papillomaviruses (α-HPVs) display the ability to downregulate many of the same interferon-inducible genes. This suggests that there is a shared need between β-HPV and α-HPVs to target innate immune responses.