Beta-HPV 5 and 8 E6 Promote p300 Degradation by Blocking AKT/p300 Association

Abstract

The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (β-HPVs); however, it is generally thought that β-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and β-HPV types. Importantly, this association appears much stronger with β-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or β-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs.

Author Summary

Human papillomaviruses (HPVs) are a family of more than 100 different viruses that cause a wide range of pathologies, from benign warts to cervical cancer. One subgroup of HPVs, the beta-HPVs, have recently become a topic of interest due to their potential involvement in squamous cell skin cancer. However, unlike the HPVs involved in cervical cancer, little is known with regards to how the beta-HPVs may facilitate cellular changes that would allow cancerous lesions to develop. Here we have identified a host-cell protein, p300, which interacts strongly with the E6 oncoprotein from two beta-HPVs, HPV 5 and HPV 8. We show that this interaction subsequently blocks another cellular protein, AKT, from binding to and stabilizing p300. By blocking this association, p300 is targeted for degradation, and thus is present in lower amounts than in normal cells. Importantly, because p300 is involved in numerous cell processes such as DNA repair, cell growth, and differentiation, the potential for E6 disrupting a number of cellular signaling pathways is vast. Taken together, our findings shed new light on how the beta-HPVs may facilitate carcinogenesis.