2011年1月，Cell Research在线发表了中科院上海巴斯德研究所蓝柯研究组关于肿瘤疱疹病毒——卡波济肉瘤病毒（Kaposi’s Sarcoma associated herpesvirus，KSHV）miRNA功能研究的最新成果。
KSHV是一种重要的人类肿瘤病毒，它可以引起卡波济肉瘤（KS）、原发性渗出性淋巴瘤（PEL）、多中心性卡斯特曼病（MCD）等数种恶性肿瘤。其中KS是AIDS患者中最常见的恶性肿瘤。KSHV属于2型g-人类疱疹病毒，其基因组有140~160Kb，编码了多达90个以上的开放阅读框（ORF）和至少17个成熟的病毒miRNA。KSHV miRNA的功能研究是当前的国际研究热点，该研究首次报道了KSHV miRNA在对抗天然免疫中的作用，并揭示了KSHV miRNA可以通过调控天然免疫的关键分子参与病毒潜伏态的维持。
博士研究生梁德光等在蓝柯研究员指导下，通过生物信息学分析，预测了天然免疫中关键的调控因子IKKe是病毒编码的miR-K12-11潜在的靶分子。他们发现，miR-K12-11可以特异性下调IKKe的3‘UTR报告基因活性，并且将miR-K12-11导入相关细胞后，可以在蛋白水平显著下调IKKe表达水平。进一步研究发现，IKKe的表达水平在KSHV感染的细胞中显著下调，而用miR-K12-11特异的inhibitor处理后，IKKe表达水平得到一定回复。此外，miR-K12-11可以抑制IKKe所介导的IRF3磷酸化，从而削弱了干扰素通路和降低了细胞的抗病毒天然免疫反应。他们还发现，miR-K12-11可以抑制IKKe对KSHV裂解期的协同激活作用。
该研究得到国家973计划、国家自然科学基金、中国科学院“百人计划”和赛诺菲-安万特-中科院上海生命科学研究院优秀青年人才基金项目的资助。（生物谷Bioon.com）
生物谷推荐原文出处：
Cell Research doi: 10.1038/cr.2011.5
A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKε
Deguang Liang, Yuan Gao, Xianzhi Lin, Zhiheng He, Qinglan Zhao, Qiang Deng and Ke Lan
Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, China
Type I interferon (IFN) signaling is the principal response mediating antiviral innate immunity. IFN transcription is dependent upon the activation of transcription factors IRF3/IRF7 and NF-κB. Many viral proteins have been shown as being capable of interfering with IFN signaling to facilitate evasion from the host innate immune response. Here, we report that a viral miRNA, miR-K12-11, encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) is critical for the modulation of IFN signaling and acts through targeting I-kappa-B kinase epsilon (IKKε). Ectopic expression of miR-K12-11 resulted in decreased IKKε expression, while inhibition of miR-K12-11 was found to restore IKKε expression in KSHV-infected cells. Importantly, expression of miR-K12-11 attenuated IFN signaling by decreasing IKKε-mediated IRF3/IRF7 phosphorylation and by inhibiting the activation of IKKε-dependent IFN stimulating genes (ISGs), allowing miR-K12-11 suppression of antiviral immunity. Our data suggest that IKKε targeting by miR-K12-11 is an important strategy utilized by KSHV to modulate IFN signaling during the KSHV lifecycle, especially in latency. We also demonstrated that IKKε was able to enhance KSHV reactivation synergistically with the treatment of 12-O-tetradecanoylphorbol 13-acetate. Moreover, inhibition of miR-K12-11 enhanced KSHV reactivation induced by vesicular stomatitis virus infection. Taken together, our findings also suggest that miR-K12-11 can contribute to maintenance of KSHV latency by targeting IKKε.
Keywords: KSHV; IFN; IKKε; miR-K12-11
