title: E6 and E7 from human papillomavirus type 16 cooperate to target the PDZ protein Na/H exchange regulatory factor 1.
abstract: Previous studies have shown that the PDZ-binding motif of the E6 oncoprotein from the mucosal high-risk (HR) human papillomavirus (HPV) types plays a key role in HPV-mediated cellular transformation in in vitro and in vivo experimental models. HR HPV E6 oncoproteins have the ability to efficiently degrade members of the PDZ motif-containing membrane-associated guanylate kinase (MAGUK) family; however, it is possible that other PDZ proteins are also targeted by E6. Here, we describe a novel interaction of HPV type 16 (HPV16) E6 with a PDZ protein, Na(+)/H(+) exchange regulatory factor 1 (NHERF-1), which is involved in a number of cellular processes, including signaling and transformation. HPV16 E6 associates with and promotes the degradation of NHERF-1, and this property is dependent on the C-terminal PDZ-binding motif of E6. Interestingly, HPV16 E7, via the activation of the cyclin-dependent kinase complexes, promoted the accumulation of a phosphorylated form of NHERF-1, which is preferentially targeted by E6. Thus, both oncoproteins appear to cooperate in targeting NHERF-1. Notably, HPV18 E6 is not able to induce NHERF-1 degradation, indicating that this property is not shared with E6 from all HR HPV types. Downregulation of NHERF-1 protein levels was also observed in HPV16-positive cervical cancer-derived cell lines, such as SiHa and CaSki, as well as HPV16-positive cervical intraepithelial neoplasia (CIN). Finally, our data show that HPV16-mediated NHERF-1 degradation correlates with the activation of the phosphatidylinositol-3'-OH kinase (PI3K)/AKT signaling pathway, which is known to play a key role in carcinogenesis.
authors.affiliation: Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, France.
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.forename: Rosa
authors.initials: R
authors.lastname: Rubino
authors.forename: Mariafrancesca
authors.initials: M
authors.lastname: Scalise
authors.forename: Tarik
authors.initials: T
authors.lastname: Gheit
authors.forename: Naveed
authors.initials: N
authors.lastname: Shahzad
authors.forename: Miranda
authors.initials: M
authors.lastname: Thomas
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
authors.forename: Cesare
authors.initials: C
authors.lastname: Indiveri
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Cardone
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Reshkin
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
mesh_terms: D000818:Animals; D020868:Gene Silencing; D057809:HEK293 Cells; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D054731:PDZ Domains; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D017923:Sodium-Hydrogen Exchangers; C059731:oncogene protein E7, Human papillomavirus type 16; C093376:sodium-hydrogen exchanger regulatory factor; D019869:Phosphatidylinositol 3-Kinases