Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders.
Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders.
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DOI：
10.1038/onc.2015.364
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发表时间：
2016-06-09
期刊：
影响因子：
8
通讯作者：
Gartenhaus RB
中科院分区：
文献类型：
--
作者：
Dai B;Chen AY;Corkum CP;Peroutka RJ;Landon A;Houng S;Muniandy PA;Zhang Y;Lehrmann E;Mazan-Mamczarz K;Steinhardt J;Shlyak M;Chen QC;Becker KG;Livak F;Michalak TI;Talwani R;Gartenhaus RB
B细胞受体(BCR)信号对B细胞的发育至关重要，在B细胞肿瘤的发生中起着关键作用。越来越多的证据表明慢性丙型肝炎病毒感染与B细胞淋巴瘤有关，然而，丙型肝炎病毒引起B细胞淋巴增生性疾病的机制尚不清楚。在这里，我们证明了丙型肝炎病毒感染患者的B细胞中的丙型肝炎病毒蛋白的表达，并表明丙型肝炎病毒上调了人原代B细胞中的BCR信号。丙型肝炎病毒非结构蛋白NS3/4A与Chk2相互作用并下调其活性，调节与B细胞淋巴增生性疾病相关的靶向mRNAs网络的Hur转录后调节。有趣的是，BCR信号通路被发现具有最多的转录本，与HUR的关联增加，并被NS3/4A上调。我们的研究揭示了NS3/4A在丙型肝炎病毒感染过程中调节宿主BCR信号中的一个先前未知的角色，有助于更好地理解丙型肝炎相关B细胞淋巴增生性疾病的分子机制。
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.