title: Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders.
abstract: B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dai
authors.affiliation: Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada.
authors.forename: A Y
authors.initials: AY
authors.lastname: Chen
authors.affiliation: Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada.
authors.forename: C P
authors.initials: CP
authors.lastname: Corkum
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Peroutka
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Landon
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Houng
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Muniandy
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lehrmann
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mazan-Mamczarz
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Steinhardt
authors.affiliation: Department of Infectious Diseases, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shlyak
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Q C
authors.initials: QC
authors.lastname: Chen
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Livak
authors.affiliation: Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada.
authors.forename: T I
authors.initials: TI
authors.lastname: Michalak
authors.affiliation: Department of Infectious Diseases, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Talwani
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.|Veterans Administration Medical Center, Baltimore, MD, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D016174:Hepacivirus / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D017361:Viral Nonstructural Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C000614516:NS3-4A serine protease, Hepatitis C virus; D057057:Serine Proteases