Inhibition of TGF-β and NOTCH Signaling by Cutaneous Papillomaviruses

Abstract

Infections with cutaneous papillomaviruses have been linked to cutaneous squamous cell carcinomas that arise in patients who suffer from a rare genetic disorder, epidermodysplasia verruciformis, or those who have experienced long-term, systemic immunosuppression following organ transplantation. The E6 proteins of the prototypical cutaneous human papillomavirus (HPV) 5 and HPV8 inhibit TGF-β and NOTCH signaling. The Mus musculus papillomavirus 1, MmuPV1, infects laboratory mouse strains and causes cutaneous skin warts that can progress to squamous cell carcinomas. MmuPV1 E6 shares biological and biochemical activities with HPV8 E6 including the ability to inhibit TGF-β and NOTCH signaling by binding the SMAD2/SMAD3 and MAML1 transcription factors, respectively. Inhibition of TGF-β and NOTCH signaling is linked to delayed differentiation and sustained proliferation of differentiating keratinocytes. Furthermore, the ability of MmuPV1 E6 to bind MAML1 is necessary for wart and cancer formation in experimentally infected mice. Hence, experimental MmuPV1 infection in mice will be a robust and valuable experimental system to dissect key aspects of cutaneous HPV infection, pathogenesis, and carcinogenesis.