A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKε
A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKε
复制标题
人类疱疹病毒 miRNA 减弱干扰素信号传导，并通过靶向 IKKÉ 有助于维持病毒潜伏期
DOI：
10.1038/cr.2011.5
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发表时间：
2011-05-01
期刊：
影响因子：
44.1
通讯作者：
Lan, Ke
中科院分区：
文献类型：
--
作者：
Liang, Deguang;Gao, Yuan;Lan, Ke
I型干扰素（IFN）信号传导是介导抗病毒先天免疫的主要应答。IFN的转录依赖于转录因子IRF 3/IRF 7和NF-κ B的激活。许多病毒蛋白已被证明能够干扰IFN信号传导，以促进逃避宿主先天免疫应答。在这里，我们报告了一种由卡波西肉瘤相关疱疹病毒（KSHV）编码的病毒miRNA，miR-K12-11，对IFN信号的调节至关重要，并通过靶向I-κ-B激酶α（IKK α）发挥作用。miR-K12-11的异位表达导致IKK β表达降低，而发现miR-K12-11的抑制可恢复KSHV感染细胞中IKK β的表达。重要的是，miR-K12-11的表达通过降低IKK ε介导的IRF 3/IRF 7磷酸化和通过抑制IKK ε依赖性IFN刺激基因（ISG）的活化来减弱IFN信号传导，从而允许miR-K12-11抑制抗病毒免疫。我们的数据表明，通过miR-K12-11靶向IKK β是KSHV在KSHV生命周期中调节IFN信号传导的重要策略，特别是在潜伏期。我们还证明，IKK β能够增强KSHV的再激活与12-O-十四酰基佛波醇13-乙酸酯的治疗协同。此外，miR-K12-11的抑制增强了由水疱性口炎病毒感染诱导的KSHV再活化。综上所述，我们的研究结果还表明，miR-K12-11可以通过靶向IKK β来维持KSHV潜伏期。
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-kappa B. 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 (IKK epsilon). Ectopic expression of miR-K12-11 resulted in decreased IKK epsilon expression, while inhibition of miR-K12-11 was found to restore IKK epsilon expression in KSHV-infected cells. Importantly, expression of miR-K12-11 attenuated IFN signaling by decreasing IKK epsilon-mediated IRF3/IRF7 phosphorylation and by inhibiting the activation of IKK epsilon-dependent IFN stimulating genes (ISGs), allowing miR-K12-11 suppression of antiviral immunity. Our data suggest that IKK epsilon 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 IKK epsilon 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 IKK epsilon.