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微小RNA-99家族通过促进IGF-1R/PI3K/Akt/mTOR/ULK1信号诱导的自噬来调节乙型肝炎病毒复制。

The microRNA-99 family modulates hepatitis B virus replication by promoting IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy.

作者信息

Lin Yong, Deng Wanyu, Pang Jinke, Kemper Thekla, Hu Jing, Yin Jian, Zhang Jiming, Lu Mengji

机构信息

Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Wuxi Medical School, Jiangnan University, Wuxi, China.

出版信息

Cell Microbiol. 2017 May;19(5). doi: 10.1111/cmi.12709. Epub 2017 Jan 5.

Abstract

MicroRNAs are small highly conserved noncoding RNAs that are widely expressed in multicellular organisms and participate in the regulation of various cellular processes including autophagy and viral replication. Evidently, microRNAs are able to modulate host gene expression and thereby inhibit or enhance hepatitis B virus (HBV) replication. The miR-99 family members are highly expressed in the liver. Interestingly, the plasma levels of miR-99 family in the peripheral blood correspond with HBV DNA loads. Thus, we asked whether the miR-99 family regulated HBV replication and analyzed the underlying molecular mechanism. Compared with primary hepatocytes, miR-99 family expression was downregulated in hepatoma cells. Transfection of miR-99a, miR-99b, and miR-100 markedly increased HBV replication, progeny secretion, and antigen expression in hepatoma cells. However, miR-99 family had no effect on HBV transcription and HBV promoter activities, suggesting that they regulate HBV replication at posttranscriptional steps. Consistent with bioinformatic analysis and recent reports, ectopic expression of miR-99 family attenuated IGF-1R/Akt/mTOR pathway signaling and repressed insulin-stimulated activation in hepatoma cells. Moreover, the experimental data demonstrated that the miR-99 family promoted autophagy through mTOR/ULK1 signaling and thereby enhanced HBV replication. In conclusion, the miR-99 family promotes HBV replication posttranscriptionally through IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy.

摘要

微小RNA是一类高度保守的小非编码RNA,广泛存在于多细胞生物中,并参与包括自噬和病毒复制在内的各种细胞过程的调控。显然,微小RNA能够调节宿主基因表达,从而抑制或增强乙型肝炎病毒(HBV)的复制。miR-99家族成员在肝脏中高表达。有趣的是,外周血中miR-99家族的血浆水平与HBV DNA载量相对应。因此,我们探究miR-99家族是否调控HBV复制,并分析其潜在的分子机制。与原代肝细胞相比,miR-99家族在肝癌细胞中的表达下调。将miR-99a、miR-99b和miR-100转染到肝癌细胞中,可显著增加HBV复制、子代分泌及抗原表达。然而,miR-99家族对HBV转录和HBV启动子活性没有影响,这表明它们在转录后水平调控HBV复制。与生物信息学分析及近期报道一致,miR-99家族的异位表达减弱了肝癌细胞中IGF-1R/Akt/mTOR信号通路,并抑制胰岛素刺激的激活。此外,实验数据表明,miR-99家族通过mTOR/ULK1信号通路促进自噬,从而增强HBV复制。总之,miR-99家族通过IGF-1R/PI3K/Akt/mTOR/ULK1信号诱导的自噬在转录后促进HBV复制。

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