Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
PLoS Pathog. 2011 Aug;7(8):e1002211. doi: 10.1371/journal.ppat.1002211. Epub 2011 Aug 25.
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.
高危型α 人乳头瘤病毒（α-HPV），如 HPV16 中的 E6 癌蛋白，其与宿主细胞蛋白的相互作用及其导致的信号通路中断已得到充分研究。而β 型人乳头瘤病毒（β-HPV）E6 的相互作用伙伴则知之甚少；然而，一般认为β-HPV E6 蛋白不会与许多已知与 α-HPV E6 结合的蛋白相互作用。在这里，我们鉴定出 p300 是一种与 α-HPV 和 β-HPV 类型的 E6 都直接相互作用的蛋白。重要的是，这种结合在β-HPV 5 型和 8 型-E6 中比在 α-HPV 16-E6 或β-HPV 38-E6 中要强得多。我们证明，5/8-E6 与 p300 之间增强的关联导致 p300 在蛋白酶体依赖性但 E6AP 非依赖性的方式下降解。相反，5/8-E6 抑制 AKT 与 p300 的结合，这是确保 p300 在细胞内稳定所必需的事件。最后，我们证明 p300 蛋白水平的降低同时影响下游信号事件，例如分化标志物 K1、K10 和内披蛋白的表达。总之，这些结果表明，β-HPV E6 蛋白能够以与 α-HPV 不同的方式影响宿主细胞信号。
