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Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders

机译:丙型肝炎病毒上调B细胞受体信号传导:HCV相关的B细胞淋巴组织增生性疾病的新机制

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摘要

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.
机译:B细胞受体(BCR)信号对于B细胞的发育至关重要,并且在B细胞瘤形成中起关键作用。越来越多的证据表明,慢性丙型肝炎病毒(HCV)感染与B细胞淋巴瘤之间存在关联,但是,HCV引起B细胞淋巴增生性疾病的机制仍不清楚。在本文中,我们证明了HCV感染患者的B细胞中HCV病毒蛋白的表达,并表明HCV上调了人类原代B细胞中的BCR信号传导。 HCV非结构蛋白NS3 / 4A与CHK2相互作用并下调其活性,从而调节与B细胞淋巴增生性疾病相关的靶标mRNA网络的HuR转录后调控。有趣的是,发现BCR信号通路的转录物数量最多,并且与HuR的关联性增加,并且被NS3 / 4A上调。我们的研究揭示了在HCV感染过程中NS3 / 4A在调节宿主BCR信号中的未知作用,有助于更好地理解与HCV相关的B细胞淋巴增生性疾病的分子机制。

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