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J Virol. 2019 Oct 9. pii: JVI.00663-19. doi: 10.1128/JVI.00663-19. [Epub ahead of print]

PDZ Domain-Containing Protein NHERF-2 is a Novel Target of Human Papillomavirus type 16 (HPV-16) and HPV-18.

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Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34149 Trieste, Italy.
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia


Cancer-causing HPV E6 oncoproteins have a Class I PDZ-binding motif (PBM) on their C-terminus, which plays critical roles that are related to HPV life cycle and HPV-induced malignancies. E6 oncoproteins use these PBMs to interact with, and target for proteasome-mediated degradation, a plethora of cellular substrates that contain PDZ domains and which are involved in the regulation of various cellular pathways. In this study, we show that both HPV-16 and HPV-18 E6 can interact with Na+/H+ exchange regulatory factor 2 (NHERF-2), a PDZ domain-containing protein, which among other cellular functions also behaves as a tumor suppressor regulating endothelial proliferation. The interaction between the E6 oncoproteins and NHERF-2 is PBM-dependent and results in proteasome-mediated degradation of NHERF-2. We further confirmed this effect in cells derived from HPV-16 and HPV-18 positive cervical tumors, where we show that NHERF-2 protein turnover is increased in the presence of E6. Finally, our data indicate that E6-mediated NHERF-2 degradation results in p27 downregulation and cyclin D1 upregulation, leading to accelerated cellular proliferation. To our knowledge, this is the first report to demonstrate that E6 oncoproteins can stimulate cell proliferation by indirectly regulating p27 via targeting a PDZ domain-containing protein.IMPORTANCE This study links HPV-16 and HPV-18 E6 oncoproteins to the modulation of cellular proliferation. The PDZ domain-containing protein NHERF-2 is a tumor suppressor, shown to regulate endothelial proliferation, and here we demonstrate that NHERF-2 is targeted by HPV E6 for proteasome-mediated degradation. Interestingly, this indirectly affects p27, cyclin D1 and CDK4 protein levels and consequently affects cell proliferation. Hence, this study provides information that will improve our understanding of the molecular basis for HPV E6 function, and it also highlights the importance of the PDZ domain-containing protein NHERF2 and its tumor suppressive role in regulating cell proliferation.


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