Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway

Area of Science:

• Virology
• Immunology
• Oncology

Background:

• Beta genus human papillomaviruses (β-HPVs) are double-stranded DNA viruses linked to skin cancer.
• β-HPV E6 expression increases micronuclei, which typically trigger innate immune responses.
• β-HPV 8 E6 paradoxically promotes proliferation instead of cell elimination.

Purpose of the Study:

• To investigate the mechanism by which β-HPV 8 E6 promotes proliferation despite inducing micronuclei.
• To test the hypothesis that β-HPV 8 E6 attenuates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway.

Main Methods:

• Stimulation of cells with pLVX-GFP plasmid.
• Immunoblot experiments to assess cGAS-STING pathway activation.
• RNA-sequencing to analyze innate immune gene expression.
• Microscopy to observe cGAS recruitment to micronuclei.

Main Results:

• β-HPV 8 E6 reduced the magnitude and intensity of cGAS-STING pathway activation.
• Impairment of the cGAS-STING pathway was most significant downstream of STING phosphorylation.
• RNA-sequencing indicated downregulation of other innate immune pathways by β-HPV 8 E6.
• cGAS was observed to be recruited to β-HPV 8 E6-induced micronuclei.

Conclusions:

• β-HPV 8 E6 attenuates the cGAS-STING innate immune response, allowing proliferation of genome-destabilized cells.
• This immune evasion mechanism may contribute to the prevalence of β-HPV infections.
• Understanding this interaction is crucial for developing strategies against β-HPV-associated skin cancers.