Beta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 association

Area of Science:

• Virology
• Molecular Biology
• Oncology

Background:

• High-risk alpha-human papillomaviruses (α-HPVs) E6 oncoproteins are well-studied for host-cell interactions and disrupted signaling pathways.
• Interactions of beta-human papillomaviruses (β-HPVs) E6 oncoproteins are less understood, with the belief they interact with fewer host proteins than α-HPV E6.

Purpose of the Study:

• To identify novel interacting partners of β-HPV E6 oncoproteins.
• To characterize the interaction between β-HPV E6 and the p300 protein.
• To elucidate the mechanism by which β-HPV E6 affects host-cell signaling.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions.
• Western blotting to assess protein levels and degradation.
• Analysis of downstream signaling events and differentiation markers.

Main Results:

• p300 was identified as a direct interacting partner for both α-HPV and β-HPV E6 oncoproteins.
• The association between β-HPV types 5 and 8 E6 and p300 was significantly stronger compared to α-HPV 16 E6 or β-HPV 38 E6.
• Enhanced binding of 5/8-E6 to p300 resulted in proteasomal-dependent degradation of p300, independent of E6AP.
• 5/8-E6 inhibited AKT association with p300, leading to p300 destabilization.
• Decreased p300 levels affected downstream signaling, including the expression of differentiation markers K1, K10, and Involucrin.

Conclusions:

• β-HPV E6 oncoproteins interact with and degrade p300 through a mechanism involving AKT inhibition.
• This interaction leads to altered host-cell signaling and differentiation.
• β-HPV E6 utilizes a unique mechanism to modulate host-cell functions, distinct from α-HPVs.