武汉病毒所《Nature Cell Biology》microRNA与病毒复制机制

　　

生物通报道，来自德州大学健康科学中心，武汉病毒所肿瘤病毒研究组，北京中国科学院研究生院，韩国Konkuk大学生物技术系的科学家们在最新一期的Nature Cell Biology上发表研究成果文章。

 

文章通讯作者是来自德州大学健康科学中心的Shou-Jiang Gao教授，他同时在武汉病毒研究所病毒学国家重点实验室任职。Gao是Greehey儿童癌症研究所肿瘤病毒项目组负责人，在获取的10年里，Gao主要从事卡波氏肉瘤相关疱疹病毒(KSHV)课题的研究。

 

卡波氏肉瘤相关疱疹病毒(KSHV) 又称人疱疹病毒8型(HHV-8)， 它是一种新的人类肿瘤病毒，是1994年美国学者Chang等首先从AIDS患者卡波氏肉瘤(KS)组织中发现的一种新的肿瘤病毒，目前被认为是KS的致病因子。KS是AIDS患者最易患的一种血管瘤，在AIDS患者中的发病率可高达50%。

 

据研究发现，KSHV在感染人类的潜伏期内，病毒的裂解性复制是维持病毒活性的关键机制，一旦经过这一时期，KSHV就可以侵入宿主的免疫系统，并诱导肿瘤发生。

 

在本研究中，Gao等人发现，用遗传学手段改造卡波氏肉瘤相关疱疹病毒基因组，将基因组上的14microRNA簇删除掉后导致病毒裂解性复制活动增强，这一过程通过抑制NF-kB活性来实现。

 

进一步对这个miRNA簇功能进行深入研究发现，14microRNA簇通过抑制IkBα蛋白的表达活性达到抑制NF-kB通路的作用。通过计算机和miRNA种子诱变分析发现，卡波氏肉瘤相关疱疹病毒的miR-K1具有直接调控IkBα蛋白表达的功能。重新表达miR-K1可重新激活NF-kB信号，并抑制病毒裂解复制活性。相反，如果抑制miR-K1的功能，则取得相反的结果。

 

这些结果表明，卡波氏肉瘤相关疱疹病毒编码一种microRNA经NF-kB来控制病毒复制过程。这些结果表明，在卡波氏肉瘤相关疱疹病毒复制过程中，miRNA具有重要的调节作用。

（生物通 张欢）

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Regulation of NF-κB inhibitor IκBα and viral replication by a KSHV microRNA

Xiufen Lei1,2,7, Zhiqiang Bai1,2,3,4,7, Fengchun Ye1,2, Jianping Xie1,2, Chan-Gil Kim1,5, Yufei Huang1,6 & Shou-Jiang Gao1,2,3,4

 

【Abstract】

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immune deficiency syndrome-related malignancies, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease1. Control of viral lytic replication is essential for KSHV latency, evasion of the host immune system and induction of tumours1. Here, we show that deletion of a 14 microRNA (miRNA) cluster from the KSHV genome significantly enhances viral lytic replication as a result of reduced NF-κB activity. The miRNA cluster regulates the NF-κB pathway by reducing expression of IκBα protein, an inhibitor of NF-κB complexes. Computational and miRNA seed mutagenesis analyses were used to identify KSHV miR-K1, which directly regulates the IκBα protein level by targeting the 3′UTR of its transcript. Expression of miR-K1 is sufficient to rescue NF-κB activity and inhibit viral lytic replication, whereas inhibition of miR-K1 in KSHV-infected PEL cells has the opposite effect. Thus, KSHV encodes an miRNA to control viral replication by activating the NF-κB pathway. These results demonstrate an important role for KSHV miRNAs in regulating viral latency and lytic replication by manipulating the host survival pathway.

 

Tumor Virology Program, Greehey Children's Cancer Research Institute, and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Department of Pediatrics, Microbiology and Immunology, Medicine, and Molecular Medicine, and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.

Graduate University of the Chinese Academy of Sciences, Beijing 100039, China.

Department of Biotechnology, Konkuk University, Chungju 380-701, Korea.

Department of Electrical and Computer Engineering, The University of Texas at San Antonio, San Antonio, TX 78249, USA.

These authors contributed equally to this work.