title: Role of phosphatidylinositol 4-phosphate (PI4P) and its binding protein GOLPH3 in hepatitis C virus secretion.
abstract: Hepatitis C virus (HCV) RNA replicates within the ribonucleoprotein complex, assembled on the endoplasmic reticulum (ER)-derived membranous structures closely juxtaposed to the lipid droplets that facilitate the post-replicative events of virion assembly and maturation. It is widely believed that the assembled virions piggy-back onto the very low density lipoprotein particles for secretion. Lipid phosphoinositides are important modulators of intracellular trafficking. Golgi-localized phosphatidylinositol 4-phosphate (PI4P) recruits proteins involved in Golgi trafficking to the Golgi membrane and promotes anterograde transport of secretory proteins. Here, we sought to investigate the role of Golgi-localized PI4P in the HCV secretion process. Depletion of the Golgi-specific PI4P pool by Golgi-targeted PI4P phosphatase hSac1 K2A led to significant reduction in HCV secretion without any effect on replication. We then examined the functional role of a newly identified PI4P binding protein GOLPH3 in the viral secretion process. GOLPH3 is shown to maintain a tensile force on the Golgi, required for vesicle budding via its interaction with an unconventional myosin, MYO18A. Silencing GOLPH3 led to a dramatic reduction in HCV virion secretion, as did the silencing of MYO18A. The reduction in virion secretion was accompanied by a concomitant accumulation of intracellular virions, suggesting a stall in virion egress. HCV-infected cells displayed a fragmented and dispersed Golgi pattern, implicating involvement in virion morphogenesis. These studies establish the role of PI4P and its interacting protein GOLPH3 in HCV secretion and strengthen the significance of the Golgi secretory pathway in this process.
authors: Division of Infectious Diseases, Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors: Bryan
authors: B
authors: Bishé
authors: Gulam H
authors: GH
authors: Syed
authors: Seth J
authors: SJ
authors: Field
authors: Aleem
authors: A
authors: Siddiqui
mesh_terms: D001693:Biological Transport, Active / Q000235:genetics; D045744:Cell Line, Tumor; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000235:genetics / Q000378:metabolism; D057074:Virus Release / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009218:Myosins; D018129:Phosphatidylinositol Phosphates; C429024:GOLPH3 protein, human; C416669:Sac1 protein, mammalian; C037178:phosphatidylinositol 4-phosphate; C407152:MYO18A protein, human