Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
J Virol. 2015 Jan;89(1):415-27. doi: 10.1128/JVI.02591-14. Epub 2014 Oct 15.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus with latent and lytic reactivation cycles. The mechanism by which KSHV evades the innate immune system to establish latency has not yet been precisely elucidated. Toll-like receptors (TLRs) are the first line of defense against viral infections. Myeloid differentiation factor 88 (MyD88) is a key adaptor that interacts with all TLRs except TLR3 to produce inflammatory factors and type I interferons (IFNs), which are central components of innate immunity against microbial infection. Here, we found that KSHV replication and transcription activator (RTA), which is an immediate-early master switch protein of viral cycles, downregulates MyD88 expression at the protein level by degrading MyD88 through the ubiquitin (Ub)-proteasome pathway. We identified the interaction between RTA and MyD88 in vitro and in vivo and demonstrated that RTA functions as an E3 ligase to ubiquitinate MyD88. MyD88 also was repressed at the early stage of de novo infection as well as in lytic reactivation. We also found that RTA inhibited lipopolysaccharide (LPS)-triggered activation of the TLR4 pathway by reducing IFN production and NF-κB activity. Finally, we showed that MyD88 promoted the production of IFNs and inhibited KSHV LANA-1 gene transcription. Taken together, our results suggest that KSHV RTA facilitates the virus to evade innate immunity through the degradation of MyD88, which might be critical for viral latency control.
MyD88 is an adaptor for all TLRs other than TLR3, and it mediates inflammatory factors and IFN production. Our study demonstrated that the KSHV RTA protein functions as an E3 ligase to degrade MyD88 through the ubiquitin-proteasome pathway and block the transmission of TLRs signals. Moreover, we found that KSHV inhibited MyD88 expression during the early stage of de novo infection as well as in lytic reactivation. These results provide a potential mechanism for the virus to evade innate immunity.
卡波氏肉瘤相关疱疹病毒（KSHV）是一种人类γ疱疹病毒，具有潜伏和裂解再激活周期。KSHV 逃避先天免疫系统建立潜伏的机制尚未精确阐明。Toll 样受体（TLRs）是抵抗病毒感染的第一道防线。髓样分化因子 88（MyD88）是与除 TLR3 之外的所有 TLR 相互作用的关键衔接蛋白，可产生炎症因子和 I 型干扰素（IFNs），它们是先天免疫抵抗微生物感染的核心成分。在这里，我们发现 KSHV 复制和转录激活剂（RTA），即病毒周期的即时早期主开关蛋白，通过泛素（Ub）-蛋白酶体途径降解 MyD88，从而在蛋白水平下调 MyD88 表达。我们在体外和体内鉴定了 RTA 与 MyD88 之间的相互作用，并证明 RTA 作为 E3 连接酶使 MyD88 泛素化。在从头感染的早期以及裂解再激活过程中，MyD88 也受到抑制。我们还发现，RTA 通过减少 IFN 产生和 NF-κB 活性来抑制脂多糖（LPS）触发的 TLR4 途径的激活。最后，我们表明，MyD88 通过促进 IFN 的产生和抑制 KSHV LANA-1 基因转录来抑制 KSHV 的复制。总之，我们的研究结果表明，KSHV RTA 通过降解 MyD88 促进病毒逃避先天免疫，这可能对病毒潜伏控制至关重要。
MyD88 是除 TLR3 之外的所有 TLR 的衔接蛋白，它介导炎症因子和 IFN 的产生。我们的研究表明，KSHV RTA 蛋白通过泛素-蛋白酶体途径作为 E3 连接酶发挥作用，降解 MyD88 并阻断 TLR 信号的传递。此外，我们发现 KSHV 在从头感染的早期以及裂解再激活过程中抑制 MyD88 的表达。这些结果为病毒逃避先天免疫提供了一种潜在的机制。
