Enhanced sensitivity to cholera toxin in ADP-ribosylarginine hydrolase-deficient mice
Enhanced sensitivity to cholera toxin in ADP-ribosylarginine hydrolase-deficient mice
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DOI：
10.1128/mcb.00302-07
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Moss, Joel
中科院分区：
文献类型：
--
作者：
Kato, Jiro;Zhu, Jianfeng;Moss, Joel
由霍乱弧菌产生的霍乱毒素（CT）通过催化肠G（s）蛋白（G（s alpha））的α亚基的ADP-核糖基化，导致特征性的水和电解质损失，从而引起霍乱的毁灭性腹泻。哺乳动物细胞含有类似于CT的ADP-核糖基转移酶和ADP-核糖基（精氨酸）蛋白水解酶（ADPRH），其切割ADP-核糖-（精氨酸）蛋白键，再生天然蛋白并完成ADP-核糖基化循环。我们推测ADPRH可能通过逆转G（s α）的ADP-核糖基化来对抗中毒。中毒对小鼠ADPRH（-/-）细胞的影响大于对野生型细胞的影响，并且通过在ADPRH（-/-）细胞中过表达野生型ADPRH而显著降低，如ADP-核糖-精氨酸含量和G（s α）修饰所证明的。同样，ADPRH（-/-）小鼠的肠袢比野生型小鼠对毒素对体液蓄积、G（s α）修饰和ADP-核糖基精氨酸含量的影响更敏感。因此，CT催化的细胞蛋白的ADP核糖基化可以被ADPRH抵消，ADPRH可以在疾病中起修饰基因的作用。此外，我们的研究表明，细菌毒素ADP-核糖基转移酶和宿主ADP-核糖基化循环之间存在酶促串扰。在疾病中，毒素催化的ADP-核糖基化破坏了这种潜在的宿主防御系统，导致ADP-核糖基化的持续和细胞的中毒。
Cholera toxin (CT) produced by Vibrio cholerae causes the devastating diarrhea of cholera by catalyzing the ADP-ribosylation of the alpha subunit of the intestinal G(s) protein (G(s alpha)), leading to characteristic water and electrolyte losses. Mammalian cells contain ADP-ribosyltransferases similar to CT and an ADP-ribosyl(arginine)protein hydrolase (ADPRH), which cleaves the ADP-ribose-(arginine) protein bond, regenerating native protein and completing an ADP-ribosylation cycle. We hypothesized that ADPRH might counteract intoxication by reversing the ADP-ribosylation of G(s alpha). Effects of intoxication on murine ADPRH(-/-) cells were greater than those on wild-type cells and were significantly reduced by overexpression of wild-type ADPRH in ADPRH(-/-) cells, as evidenced by both ADP-ribose-arginine content and G(s alpha) modification. Similarly, intestinal loops in the ADPRH(-/-) mouse were more sensitive than their wild-type counterparts to toxin effects on fluid accumulation, G(s alpha) modification, and ADP-ribosylarginine content. Thus, CT-catalyzed ADP-ribosylation of cell proteins can be counteracted by ADPRH, which could function as a modifier gene in disease. Further, our study demonstrates that enzymatic cross talk exists between bacterial toxin ADP-ribosyltransferases and host ADP-ribosylation cycles. In disease, toxin-catalyzed ADP-ribosylation overwhelms this potential host defense system, resulting in persistence of ADP-ribosylation and intoxication of the cell.