High-risk human papillomavirus E6 oncoproteins interact with 14-3-3ζ in a PDZ binding motif-dependent manner.
نویسندگان
چکیده
Cervical cancer develops through the combined activities of the human papillomavirus (HPV) E6 and E7 oncoproteins. A defining characteristic of E6 oncoproteins derived from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at the extreme carboxy terminus of the protein which is absent from E6 proteins derived from the so-called low-risk HPV types. Within this PBM is also a protein kinase A (PKA) phospho-acceptor site, which is thought to negatively regulate the association of E6 with its PDZ domain-containing substrates. We can now show that phosphorylation of E6 by PKA and/or AKT confers the ability to interact with 14-3-3ζ. The interaction is direct and specific for the high-risk HPV E6 oncoproteins, although there are significant differences in the efficiencies with which HPV-16, HPV-18, and HPV-31 E6 oncoproteins can associate with 14-3-3ζ; this correlates directly with their respective susceptibilities to phosphorylation by PKA and/or AKT. We demonstrate here that the interaction between E6 and 14-3-3ζ also requires integrity of the E6 PBM, and downregulation of 14-3-3ζ results in a marked reduction in the levels of HPV-18 E6 expression in HeLa cells. Using phospho-specific anti-E6 antibodies, we also demonstrate significant levels of E6 phosphorylation in vivo. These studies redefine the potential relevance of the E6 PBM in the development of cervical cancer, suggesting that interaction with 14-3-3ζ, as well as the more well-established interactions with PDZ domain-containing substrates, is likely to be responsible for the biological activities attributed to this region of the high-risk HPV E6 oncoproteins.
منابع مشابه
Cancer-causing human papillomavirus E6 proteins display major differences in the phospho-regulation of their PDZ interactions.
UNLABELLED Previous studies have shown that the cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins have PDZ binding potential, an activity which is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions are not constitutive, and they can be negatively regulated by phosphorylation within the E6 PDZ b...
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ورودعنوان ژورنال:
- Journal of virology
دوره 87 3 شماره
صفحات -
تاریخ انتشار 2013