Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication.

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Date

2017-06-27

Author

Tsai, YC
Kotiya, A
Kiriş, Erkan
Yang, M
Bavari, S
Tessarollo, L
Oyler, GA
Weissman, AM

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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.

Subject Keywords

Synaptosomal-associated protein 25, Synaptic transmission, Motoneuron, USP9X, Toxin persistence

URI

https://hdl.handle.net/11511/42632

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

https://doi.org/10.1073/pnas.1621076114

Collections

Department of Biology, Article

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Citation Formats

Y. Tsai et al., “Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication.,” Proceedings of the National Academy of Sciences of the United States of America, 2017, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/42632.