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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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B-Lymphocytes / metabolism*
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Checkpoint Kinase 2 / metabolism
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Down-Regulation
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HeLa Cells
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Hepacivirus / metabolism*
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Hepatitis C, Chronic / blood
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Hepatitis C, Chronic / genetics
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Hepatitis C, Chronic / metabolism*
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Hepatitis C, Chronic / virology
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Humans
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Lymphoma, Large B-Cell, Diffuse / blood
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / virology
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Lymphoproliferative Disorders / blood
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / metabolism
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Lymphoproliferative Disorders / virology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Antigen, B-Cell / genetics
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Receptors, Antigen, B-Cell / metabolism*
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Serine Proteases / genetics
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Serine Proteases / metabolism
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Signal Transduction
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Up-Regulation
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism
Substances
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RNA, Messenger
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Receptors, Antigen, B-Cell
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Viral Nonstructural Proteins
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Checkpoint Kinase 2
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CHEK2 protein, human
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NS3-4A serine protease, Hepatitis C virus
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Serine Proteases