title: Phosphatidylinositol-4 kinase III beta and oxysterol-binding protein accumulate unesterified cholesterol on poliovirus-induced membrane structure.
abstract: Studies on anti-picornavirus compounds have revealed an essential role of a novel cellular pathway via host phosphatidylinositol-4 kinase III beta (PI4KB) and oxysterol-binding protein (OSBP) family I in poliovirus (PV) replication. However, the molecular role for this pathway in PV replication has yet to be determined. Here, viral and host proteins modulating production of phosphatidylinositol 4-phosphate (PI4P) and accumulation of unesterified cholesterol (UC) in cells were analyzed and the role of the PI4KB/OSBP pathway in PV replication characterized. Virus protein 2BC was identified as a novel interactant of PI4KB. PI4KB and VCP/p97 bind to a partially overlapped region of 2BC with different sensitivity to a 2C inhibitor. Production of PI4P and accumulation of UC were enhanced by virus protein 2BC, but suppressed by virus proteins 3A and 3AB. In PV-infected cells, a PI4KB inhibitor suppressed production of PI4P, and both a PI4KB inhibitor and an OSBP ligand suppressed accumulation of UC on virus-induced membrane structure. Inhibition of PI4KB activity caused dissociation of OSBP from virus-induced membrane structure in PV-infected cells. Synthesis of viral nascent RNA in PV-infected cells was not affected in the presence of PI4KB inhibitor and OSBP ligand; however, transient pre-treatment of PV-infected cells with these inhibitors suppressed viral RNA synthesis. These results suggest that virus proteins modulate PI4KB activity and provide PI4P for recruitment of OSBP to accumulate UC on virus-induced membrane structure for formation of a virus replication complex.
authors: Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-Shi, Tokyo, 208-0011, Japan.
authors: Minetaro
authors: M
authors: Arita
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism* / Q000821:virology*; D002784:Cholesterol / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017955:Poliovirus / Q000502:physiology*; D025941:Protein Interaction Mapping; D011987:Receptors, Steroid / Q000378:metabolism*; D014779:Virus Replication; D000098825:Oxysterol Binding Proteins
chemical_list: D002784:Cholesterol; D017853:Phosphotransferases (Alcohol Group Acceptor); D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C581087:PI4KB protein, human
keywords: enterovirus; oxysterol-binding protein; phosphatidylinositol-4 kinase III beta; replication