Viral Macro Domains Reverse Protein ADP-Ribosylation
Viral Macro Domains Reverse Protein ADP-Ribosylation
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DOI：
10.1128/jvi.00705-16
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发表时间：
2016-10-01
影响因子：
5.4
通讯作者：
Canard, Bruno
中科院分区：
文献类型：
--
作者：
Li, Changqing;Debing, Yannick;Canard, Bruno
ADP-核糖基化是一种蛋白质翻译后修饰，其中ADP-核糖从NAD（+）转移到特异性受体以调节多种细胞过程。宏结构域是一个古老的和高度进化保守的蛋白质结构域，广泛分布在所有生命王国，包括病毒。人TARG 1/C6 orf 130、MacroD 1和MacroD 2蛋白可通过其大结构域的水解活性作用于ADP-核糖基化底物来逆转ADP-核糖基化。在这里，我们报告说，从戊型肝炎病毒（HEV）的宏结构域作为一个ADP-核糖蛋白水解酶的单ADP-核糖（MAR）和聚（ADP-核糖）（PAR）链去除（去MARylation和去PARylation，分别）从单和聚（ADP）-核糖基化的蛋白质，分别。顺式HEV解旋酶的存在显著增加了大结构域与聚（ADP-核糖）的结合并刺激去PAR化活性。后者的废除显着减少了戊型肝炎病毒亚基因组复制子的复制。脱MARylation活性存在于所有三种携带大结构域的致病性正义单链RNA [（+）ssRNA]病毒家族中：冠状（严重急性呼吸系统综合征冠状病毒和人冠状病毒229 E）、披膜病毒科（委内瑞拉马脑炎病毒）和肝炎病毒科（HEV），提示它可能是一个重要的嗜性和/或致病性决定因子。核糖基化是以动态方式调节细胞蛋白质活性以调节和协调多种细胞过程的共价翻译后修饰。冠状病毒科、披膜病毒科和肝炎病毒科三个病毒科具有嵌入其多蛋白中的宏结构域。在这里，我们表明，病毒的宏域逆转细胞ADP-核糖基化，潜在地削减了细胞中的病毒感染的信号。各种聚（ADP-核糖）聚合酶是臭名昭著的细胞完整性的监护人，它们被来自这些病毒家族成员的宏结构域去修饰。在戊型肝炎病毒的情况下，相邻的病毒解旋酶结构域显著增加了大结构域与PAR的结合，并模拟了去修饰活性。
ADP-ribosylation is a posttranslational protein modification in which ADP-ribose is transferred from NAD(+) to specific acceptors to regulate a wide variety of cellular processes. The macro domain is an ancient and highly evolutionarily conserved protein domain widely distributed throughout all kingdoms of life, including viruses. The human TARG1/C6orf130, MacroD1, and MacroD2 proteins can reverse ADP-ribosylation by acting on ADP-ribosylated substrates through the hydrolytic activity of their macro domains. Here, we report that the macro domain from hepatitis E virus (HEV) serves as an ADP-ribose-protein hydrolase for mono-ADP-ribose (MAR) and poly(ADP-ribose) (PAR) chain removal (de-MARylation and de-PARylation, respectively) from mono-and poly(ADP)-ribosylated proteins, respectively. The presence of the HEV helicase in cis dramatically increases the binding of the macro domain to poly(ADP-ribose) and stimulates the de-PARylation activity. Abrogation of the latter dramatically decreases replication of an HEV subgenomic replicon. The de-MARylation activity is present in all three pathogenic positive-sense, single-stranded RNA [(+)ssRNA] virus families which carry a macro domain: Coronaviridae (severe acute respiratory syndrome coronavirus and human coronavirus 229E), Togaviridae (Venezuelan equine encephalitis virus), and Hepeviridae (HEV), indicating that it might be a significant tropism and/or pathogenic determinant.IMPORTANCEProtein ADP-ribosylation is a covalent posttranslational modification regulating cellular protein activities in a dynamic fashion to modulate and coordinate a variety of cellular processes. Three viral families, Coronaviridae, Togaviridae, and Hepeviridae, possess macro domains embedded in their polyproteins. Here, we show that viral macro domains reverse cellular ADP-ribosylation, potentially cutting the signal of a viral infection in the cell. Various poly(ADP-ribose) polymerases which are notorious guardians of cellular integrity are demodified by macro domains from members of these virus families. In the case of hepatitis E virus, the adjacent viral helicase domain dramatically increases the binding of the macro domain to PAR and simulates the demodification activity.