Epstein-Barr Virus-Induced miR-155 Attenuates NF-κB Signaling and Stabilizes Latent Virus Persistence
Epstein-Barr Virus-Induced miR-155 Attenuates NF-κB Signaling and Stabilizes Latent Virus Persistence
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DOI：
10.1128/jvi.00752-08
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发表时间：
2008-11-01
影响因子：
5.4
通讯作者：
Lieberman, Paul M.
中科院分区：
文献类型：
--
作者：
Lu, Fang;Weidmer, Andreas;Lieberman, Paul M.
MicroRNAs参与了对正常和癌细胞发育至关重要的基因表达程序的调节。已知MIR-155在B细胞发育中发挥作用，并在各种B细胞淋巴瘤中上调，包括几种潜伏感染EB病毒(EBV)的B细胞淋巴瘤。我们在这里表明，EBV感染原代人类B淋巴细胞导致miR-155及其前体RNA BIC的持续升高。EB病毒编码的潜伏期膜蛋白1(LMP1)可部分重建B淋巴细胞的BIC活性，但不能重建上皮细胞培养的BIC活性。LMP1是核因子-kappaB信号通路的有效激活剂，对EB病毒使B淋巴细胞永生化是必不可少的。MiR-155的抑制剂进一步刺激了核因子-kappaB反应基因的转录，ikk epsilon被认为是miR-155翻译抑制的潜在靶点。MiR-155抑制剂显著降低了潜伏感染细胞中EBNA1的mRNA和EBV的拷贝数。这表明miR-155通过调节核因子-kappaB信号和抑制宿主对潜伏病毒感染的天然免疫而导致EBV永生化。
MicroRNAs have been implicated in the modulation of gene expression programs important for normal and cancer cell development. miR-155 is known to play a role in B-cell development and is upregulated in various B-cell lymphomas, including several that are latently infected with Epstein-Barr virus (EBV). We show here that EBV infection of primary human B lymphocytes leads to the sustained elevation of miR-155 and its precursor RNA, BIC. The EBV-encoded latency membrane protein 1 (LMP1) can partially reconstitute BIC activation in B lymphocytes but not in epithelial cell cultures. LMP1 is a potent activator of NF-kappa B signaling pathways and is essential for EBV immortalization of B lymphocytes. An inhibitor to miR-155 further stimulated NF-kappa B responsive gene transcription, and IKK epsilon was identified as a potential target of miR-155 translational repression. Remarkably, miR-155 inhibitor reduced EBNA1 mRNA and the EBV copy number in latently infected cells. This suggests that miR-155 contributes to EBV immortalization by modulation of NF-kappa B signaling and the suppression of host innate immunity to latent viral infection.