Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway.

Area of Science:

• Virology
• Immunology
• Oncology

Background:

• Beta human papillomaviruses (β-HPVs) are linked to skin cancer by destabilizing host genomes.
• β-HPV 8 E6 expression causes genomic instability, yet paradoxically promotes cell proliferation.
• The mechanisms by which β-HPVs overcome anti-proliferative signals are not fully understood.

Purpose of the Study:

• To investigate the hypothesis that β-HPV 8 E6 attenuates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway.
• To determine if β-HPV 8 E6 interferes with innate immune responses to cytosolic double-stranded DNA (dsDNA).

Main Methods:

• Transfection of cells with dsDNA to activate the cGAS-STING pathway.
• Assessment of β-HPV 8 E6's effect on STING phosphorylation and cGAS-STING pathway activation intensity.
• Unbiased assessment of β-HPV 8 E6's impact on innate immunity gene expression.

Main Results:

• β-HPV 8 E6 significantly reduced cGAS-STING pathway activation intensity in response to dsDNA.
• STING phosphorylation was decreased by β-HPV 8 E6, indicating pathway attenuation.
• β-HPV 8 E6 broadly downregulated innate immune-associated genes, including interferon-inducible genes.

Conclusions:

• β-HPV 8 E6 impairs the cGAS-STING innate immune response by reducing STING phosphorylation.
• This suppression of innate immunity may contribute to β-HPV prevalence and skin cancer development.
• Both β-HPVs and α-HPVs appear to share a strategy of downregulating innate immune responses.