title: A role for retromer in hepatitis C virus replication.
abstract: Hepatitis C virus (HCV) has infected over 170 million people worldwide. Phosphatidylinositol 4-phosphate (PI4P) is the organelle-specific phosphoinositide enriched at sites of HCV replication. Whether retromer, a PI4P-related host transport machinery, unloads its cargo at HCV replication sites remains inconclusive. We sought to characterize the role of retromer in HCV replication. Here, we demonstrated the interaction between retromer subunit Vps35 and HCV NS5A protein by immunoprecipitation and GST pulldown. Vps35 colocalized with NS5A and PI4P in both OR6 replicon and JFH1 infected Huh 7.5.1 cells. HCV replication was inhibited upon silencing retromer subunits. CIMPR, a typical retromer cargo, participated in HCV replication. Our data suggest that retromer component Vps35 is recruited by NS5A to viral replication sites where PI4P unloads CIMPR. These findings demonstrate a dependence role of retromer in HCV replication and identify retromer as a potential therapeutic target against HCV.
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100176, China.
authors: Peiqi
authors: P
authors: Yin
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100176, China.
authors: Zhi
authors: Z
authors: Hong
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100176, China.
authors: Xiaojie
authors: X
authors: Yang
authors: Gastrointestinal Division, Department of Medicine, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors: Raymond T
authors: RT
authors: Chung
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100176, China. armzhang@hotmail.com.
authors: Leiliang
authors: L
authors: Zhang
mesh_terms: D002460:Cell Line; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D018129:Phosphatidylinositol Phosphates / Q000032:analysis / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000032:analysis / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018129:Phosphatidylinositol Phosphates; D033921:Vesicular Transport Proteins; D017361:Viral Nonstructural Proteins; C419573:VPS35 protein, human; C037178:phosphatidylinositol 4-phosphate; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: CIMPR; HCV; NS5A; PI4P; Retromer