Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication.
Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication.
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去泛素化酶 VCIP135 决定 A 型肉毒杆菌神经毒素中毒的持续时间。
DOI：
10.1073/pnas.1621076114
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发表时间：
2017
影响因子：
11.1
通讯作者：
Weissman,AllanM
中科院分区：
文献类型：
--
作者：
Tsai,YienChe;Kotiya,Archana;Kiris,Erkan;Yang,Mei;Bavari,Sina;Tessarollo,Lino;Oyler,GeorgeA;Weissman,AllanM
肉毒杆菌中毒的特点是弛缓性麻痹，可由七种已知肉毒神经毒素 (BoNT) 血清型中的任何一种中毒引起，所有这些都会通过 SNARE 蛋白的内切蛋白水解裂解来破坏突触传递。 A血清型BoNT（BoNT/A）具有最持久的作用，可以持续数月，并通过特异性裂解和灭活SNAP25来发挥其作用。导致中毒持续的一个主要因素是催化轻链的半衰期长，它在进入细胞后几个月仍保持酶活性。在这里，我们报告 BoNT/A 催化轻链与泛素连接酶 HECTD2 结合，并且是泛素连接酶 HECTD2 的底物。然而，轻链通过去泛素化酶 VCIP135/VCPIP1 的主导作用来逃避蛋白酶体降解。这种去泛素化酶直接结合 BoNT/A 轻链，两者在细胞中通过轻链蛋白酶的 C 端 77 个氨基酸结合。特定 DUB 抑制剂与 BoNT/A 蛋白水解活性抑制剂的开发可能有助于降低与 BoNT/A 中毒相关的发病率和公共卫生成本，并可能具有潜在的生物防御意义。
Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several months, and exerts its effects by specifically cleaving and inactivating SNAP25. A major factor contributing to the persistence of intoxication is the long half-life of the catalytic light chain, which remains enzymatically active months after entry into cells. Here we report that BoNT/A catalytic light chain binds to, and is a substrate for, the ubiquitin ligase HECTD2. However, the light chain evades proteasomal degradation by the dominant effect of a deubiquitinating enzyme, VCIP135/VCPIP1. This deubiquitinating enzyme binds BoNT/A light chain directly, with the two associating in cells through the C-terminal 77 amino acids of the light chain protease. The development of specific DUB inhibitors, together with inhibitors of BoNT/A proteolytic activity, may be useful for reducing the morbidity and public health costs associated with BoNT/A intoxication and could have potential biodefense implications.