Kaposi's Sarcoma-Associated Herpesvirus-Encoded Replication and Transcription Activator Impairs Innate Immunity via Ubiquitin-Mediated Degradation of Myeloid Differentiation Factor 88
Kaposi's Sarcoma-Associated Herpesvirus-Encoded Replication and Transcription Activator Impairs Innate Immunity via Ubiquitin-Mediated Degradation of Myeloid Differentiation Factor 88
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卡波西肉瘤相关疱疹病毒编码的复制和转录激活剂通过泛素介导的骨髓分化因子 88 降解损害先天免疫
DOI：
10.1128/jvi.02591-14
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发表时间：
2014-10
影响因子：
5.4
通讯作者：
Lan Ke
中科院分区：
文献类型：
--
作者：
Zhao Qinglan;Liang Deguang;Sun Rui;Jia Baosen;Xia Tian;Xiao Hui;Lan Ke
卡波济肉瘤相关疱疹病毒（KSHV）是一种具有潜伏和裂解再激活周期的人γ疱疹病毒。KSHV逃避先天免疫系统以建立潜伏期的机制尚未被精确阐明。Toll样受体（TLR）是抵抗病毒感染的第一道防线。髓样分化因子88（MyD 88）是一种关键的衔接子，其与除TLR 3之外的所有TLR相互作用以产生炎性因子和I型干扰素（IFN），其是针对微生物感染的先天免疫的中心组分。在这里，我们发现，KSHV复制和转录激活因子（RTA），这是一个立即早期的主开关蛋白的病毒周期，下调MyD 88的表达在蛋白质水平上通过降解MyD 88通过泛素（Ub）-蛋白酶体途径。我们在体外和体内鉴定了RTA和MyD 88之间的相互作用，并证明RTA作为E3连接酶来泛素化MyD 88。MyD 88在从头感染的早期阶段以及在裂解再活化中也被抑制。我们还发现RTA通过减少IFN的产生和NF-κB的活性来抑制脂多糖（LPS）触发的TLR 4通路的激活。最后，我们发现MyD 88促进IFN的产生并抑制KSHV拉娜-1基因的转录。综上所述，我们的研究结果表明，KSHV RTA通过降解MyD 88促进病毒逃避先天免疫，这可能是病毒潜伏期控制的关键。MyD 88是除TLR 3以外的所有TLR的接头，并且它介导炎症因子和IFN的产生。我们的研究表明，KSHV RTA蛋白作为E3连接酶，通过泛素-蛋白酶体途径降解MyD 88，并阻断TLR信号的传递。此外，我们发现，KSHV抑制MyD 88的表达在早期阶段的从头感染，以及在裂解再激活。这些结果为病毒逃避先天免疫提供了潜在的机制。
ABSTRACT 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. IMPORTANCE 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.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
3.7
作者：
Myoung J;Ganem D
通讯作者：
Ganem D
DOI：
10.4049/jimmunol.0803682
发表时间：
2009-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Zhao Y;De Trez C;Flynn R;Ware CF;Croft M;Salek-Ardakani S
通讯作者：
Salek-Ardakani S
DOI：
10.1016/0167-5699(92)90198-g
发表时间：
1992-01-01
期刊：
IMMUNOLOGY TODAY
影响因子：
--
作者：
JANEWAY, CA
通讯作者：
JANEWAY, CA
影响因子：
64.8
作者：
M. Thome;P. Schneider;K. Hofmann;H. Fickenscher;E. Meinl;F. Neipel;C. Mattmann;K. Burns;J. Bodm
通讯作者：
M. Thome;P. Schneider;K. Hofmann;H. Fickenscher;E. Meinl;F. Neipel;C. Mattmann;K. Burns;J. Bodm