2011年1月，Cell Research在線發(fā)表了中科院上海巴斯德研究所藍柯研究組關(guān)于腫瘤皰疹病毒——卡波濟肉瘤病毒（Kaposi’s Sarcoma associated herpesvirus,，KSHV）miRNA功能研究的最新成果,。
KSHV是一種重要的人類腫瘤病毒，它可以引起卡波濟肉瘤（KS）,、原發(fā)性滲出性淋巴瘤（PEL）,、多中心性卡斯特曼病（MCD）等數(shù)種惡性腫瘤,。其中KS是AIDS患者中最常見的惡性腫瘤,。KSHV屬于2型g-人類皰疹病毒，其基因組有140~160Kb,，編碼了多達90個以上的開放閱讀框（ORF）和至少17個成熟的病毒miRNA,。KSHV miRNA的功能研究是當前的國際研究熱點，該研究首次報道了KSHV miRNA在對抗天然免疫中的作用,，并揭示了KSHV miRNA可以通過調(diào)控天然免疫的關(guān)鍵分子參與病毒潛伏態(tài)的維持,。
博士研究生梁德光等在藍柯研究員指導(dǎo)下，通過生物信息學分析,，預(yù)測了天然免疫中關(guān)鍵的調(diào)控因子IKKe是病毒編碼的miR-K12-11潛在的靶分子,。他們發(fā)現(xiàn)，miR-K12-11可以特異性下調(diào)IKKe的3‘UTR報告基因活性,，并且將miR-K12-11導(dǎo)入相關(guān)細胞后,，可以在蛋白水平顯著下調(diào)IKKe表達水平。進一步研究發(fā)現(xiàn),，IKKe的表達水平在KSHV感染的細胞中顯著下調(diào),，而用miR-K12-11特異的inhibitor處理后，IKKe表達水平得到一定回復(fù),。此外,，miR-K12-11可以抑制IKKe所介導(dǎo)的IRF3磷酸化，從而削弱了干擾素通路和降低了細胞的抗病毒天然免疫反應(yīng),。他們還發(fā)現(xiàn),，miR-K12-11可以抑制IKKe對KSHV裂解期的協(xié)同激活作用,。
該研究得到國家973計劃、國家自然科學基金,、中國科學院“百人計劃”和賽諾菲-安萬特-中科院上海生命科學研究院優(yōu)秀青年人才基金項目的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
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
