title: Identification of novel human kinases that suppress hepatitis C virus infection.
abstract: The human kinome includes between 500 and 600 known kinases and open reading frames (ORFs) that play key roles in regulating many cellular processes. Past studies adopting loss-of-function approaches have identified some kinases whose activities are required for hepatitis C virus (HCV) life cycle. Here, by screening a retroviral cDNA library of 192 active human kinases, we found that three of them, namely cyclin-dependent kinases regulatory subunit 1 (CKS1B), mitogen-activated protein kinase kinase 5 (MAP2K5) and protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), potently suppressed HCV infection. The expression of these kinases did not induce the production of type I interferon (IFN) and interferon-stimulated genes (ISGs); instead, they inhibited HCV at postentry stages. Specifically, CKS1B and MAP2K5 significantly inhibited viral RNA replication. PACSIN1, by contrast, inhibited HCV infection by decreasing the level of HCV p7. Altogether, the identification of human protein kinases that exert an anti-HCV activity highlighted the potential of combating HCV infection by activating specific kinase-mediated pathways, offering an alternative strategy of treatment.
authors.affiliation: Departments of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C093090:CKS1B protein, human; D007370:Interferon Type I; C492182:PACSIN1 protein, human; D042846:CDC2-CDC28 Kinases; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human
keywords: hepatitis C virus; human kinase; viral hepatitis