title: SHIP2 regulates epithelial cell polarity through its lipid product, which binds to Dlg1, a pathway subverted by hepatitis C virus core protein.
abstract: The main targets of hepatitis C virus (HCV) are hepatocytes, the highly polarized cells of the liver, and all the steps of its life cycle are tightly dependent on host lipid metabolism. The interplay between polarity and lipid metabolism in HCV infection has been poorly investigated. Signaling lipids, such as phosphoinositides (PIs), play a vital role in polarity, which depends on the distribution and expression of PI kinases and PI phosphatases. In this study, we report that HCV core protein, expressed in Huh7 and Madin-Darby canine kidney (MDCK) cells, disrupts apicobasal polarity. This is associated with decreased expression of the polarity protein Dlg1 and the PI phosphatase SHIP2, which converts phosphatidylinositol 3,4,5-trisphosphate into phosphatidylinositol 4,5-bisphosphate (PtdIns(3,4)P2). SHIP2 is mainly localized at the basolateral membrane of polarized MDCK cells. In addition, PtdIns(3,4)P2 is able to bind to Dlg1. SHIP2 small interfering RNA or its catalytically dead mutant disrupts apicobasal polarity, similar to HCV core. In core-expressing cells, RhoA activity is inhibited, whereas Rac1 is activated. Of interest, SHIP2 expression rescues polarity, RhoA activation, and restricted core level in MDCK cells. We conclude that SHIP2 is an important regulator of polarity, which is subverted by HCV in epithelial cells. It is suggested that SHIP2 could be a promising target for anti-HCV treatment.
authors.affiliation: Université Paris-Sud, UMR-S 785, F-94800 Villejuif, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Awad
authors.forename: Sokhavuth
authors.initials: S
authors.lastname: Sar
authors.forename: Ronan
authors.initials: R
authors.lastname: Barré
authors.forename: Clotilde
authors.initials: C
authors.lastname: Cariven
authors.forename: Mickael
authors.initials: M
authors.lastname: Marin
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Salles
authors.forename: Christophe
authors.initials: C
authors.lastname: Erneux
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Ama
authors.initials: A
authors.lastname: Gassama-Diagne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D000074288:Discs Large Homolog 1 Protein; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D014758:Viral Core Proteins; C513314:DLG1 protein, human; C060974:phosphatidylinositol 3,4,5-triphosphate; C061816:phosphatidylinositol-3-phosphatase; C098706:INPPL1 protein, human