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

Bennett Saidu, Nathaniel Edward; Filić, Vedrana; Thomas, Miranda; Sarabia-Vega, Vanessa; Đukić, Anamaria; Miljković, Frane; Banks, Lawrence; Tomaić, Vjekoslav (2019) PDZ Domain-Containing Protein NHERF-2 Is a Novel Target of Human Papillomavirus 16 (HPV-16) and HPV-18. Journal of Virology, 94 (1). ISSN 0022-538X

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Abstract

Cancer-causing human papillomavirus (HPV) E6 oncoproteins have a class I PDZ-binding motif (PBM) on their C termini, which play critical roles that are related to the HPV life cycle and HPV-induced malignancies. E6 oncoproteins use these PBMs to interact with, to target for proteasome-mediated degradation, a plethora of cellular substrates that contain PDZ domains and that are involved in the regulation of various cellular pathways. In this study, we show that both HPV-16 and HPV-18 E6 oncoproteins 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 through targeting a PDZ domain-containing protein.

Item Type:	Article
Uncontrolled Keywords:	E6 oncoprotein; HPV; NHERF-2; cell proliferation; cervical cancer; cyclin D1; p27
Subjects:	BIOMEDICINE AND HEALTHCARE BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Human Genetics, Genomics and Proteomics
Divisions:	Division of Molecular Medicine
Depositing User:	Vjekoslav Tomaić
Date Deposited:	03 Dec 2020 08:54
URI:	http://fulir.irb.hr/id/eprint/6029
DOI:	10.1128/JVI.00663-19

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