title: Phosphoinositides in the hepatitis C virus life cycle.
abstract: Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P effector proteins also include the lipid-transfer and structural proteins such as ceramide transfer protein (CERT), oxysterol binding protein (OSBP) and Golgi phosphoprotein 3 (GOLPH3) that help maintain Golgi-membrane composition and structure. Depletion of Golgi-specific PI4P pools by silencing PI4KIIIβ, expression of dominant negative CERT and OSBP mutants, or silencing GOLPH3 perturb HCV secretion. In this review we highlight the role of PIPs and specifically PI4P in the HCV life cycle.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, CA 92093, USA. bbishe@ucsd.edu
authors.forename: Bryan
authors.initials: B
authors.lastname: Bishé
authors.forename: Gulam
authors.initials: G
authors.lastname: Syed
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000821:virology; D020868:Gene Silencing; D006056:Golgi Apparatus / Q000378:metabolism / Q000821:virology; D016174:Hepacivirus / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000473:pathology / Q000821:virology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D019065:Virus Assembly; D014779:Virus Replication; D000098825:Oxysterol Binding Proteins
chemical_list: D000998:Antiviral Agents; C429024:GOLPH3 protein, human; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D018129:Phosphatidylinositol Phosphates; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C037178:phosphatidylinositol 4-phosphate; C119090:CERT1 protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D017346:Protein Serine-Threonine Kinases