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首页> 外文OA文献 >The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases
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The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases

机译：基孔肯雅热病毒和其他致病性正链RNA病毒非结构蛋白的保守宏结构域起单ADP-核糖基水解酶的作用

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Human pathogenic positive single strand RNA ((+)ssRNA) viruses, including Chikungunya virus, pose severe health problems as for many neither efficient vaccines nor therapeutic strategies exist. To interfere with propagation, viral enzymatic activities are considered potential targets. Here we addressed the function of the viral macrodomains, conserved folds of non-structural proteins of many (+)ssRNA viruses. Macrodomains are closely associated with ADP-ribose function and metabolism. ADP-ribosylation is a post-translational modification controlling various cellular processes, including DNA repair, transcription and stress response. We found that the viral macrodomains possess broad hydrolase activity towards mono-ADP-ribosylated substrates of the mono-ADP-ribosyltransferases ARTD7, ARTD8 and ARTD10 (aka PARP15, PARP14 and PARP10, respectively), reverting this post-translational modification both in vitro and in cells. In contrast, the viral macrodomains possess only weak activity towards poly-ADP-ribose chains synthesized by ARTD1 (aka PARP1). Unlike poly-ADP-ribosylglycohydrolase, which hydrolyzes poly-ADP-ribose chains to individual ADP-ribose units but cannot cleave the amino acid side chain - ADP-ribose bond, the different viral macrodomains release poly-ADP-ribose chains with distinct efficiency. Mutational and structural analyses identified key amino acids for hydrolase activity of the Chikungunya viral macrodomain. Moreover, ARTD8 and ARTD10 are induced by innate immune mechanisms, suggesting that the control of mono-ADP-ribosylation is part of a host-pathogen conflict.
机译：人类致病性阳性单链RNA（（+）ssRNA）病毒（包括基孔肯雅病毒）带来严重的健康问题，因为对于许多有效疫苗和治疗策略均不存在。为了干扰繁殖，病毒酶活性被认为是潜在的靶标。在这里，我们解决了病毒宏结构域的功能，即许多（+）ssRNA病毒的非结构蛋白的保守折叠。大域与ADP核糖功能和代谢密切相关。 ADP-核糖基化是翻译后修饰，控制各种细胞过程，包括DNA修复，转录和应激反应。我们发现病毒大域对单ADP-核糖基转移酶ARTD7，ARTD8和ARTD10（分别为PARP15，PARP14和PARP10）的单ADP-核糖基化底物具有广泛的水解酶活性，在体外和体外均可恢复这种翻译后修饰在细胞中。相反，病毒大结构域对ARTD1（aka PARP1）合成的聚ADP-核糖链仅具有弱活性。不同于将聚ADP-核糖链水解为单个ADP-核糖单元但不能裂解氨基酸侧链-ADP-核糖键的聚ADP-核糖基糖基水解酶，不同的病毒大域释放出具有独特效率的聚ADP-核糖链。突变和结构分析确定了基孔肯雅病毒大结构域水解酶活性的关键氨基酸。此外，ARTD8和ARTD10是由先天免疫机制诱导的，表明对单ADP-核糖基化的控制是宿主-病原体冲突的一部分。

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