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Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5158-E5166. doi: 10.1073/pnas.1621076114. Epub 2017 Jun 5.

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

Author information

1
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; weissmaa@mail.nih.gov tsaiyien@mail.nih.gov.
2
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218.
3
Synaptic Research LLC, Halethorpe, MD 21227.
4
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702.
5
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
6
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.

Abstract

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.

KEYWORDS:

USP9X; motoneuron; synaptic transmission; synaptosomal-associated protein 25; toxin persistence

PMID:
28584101
PMCID:
PMC5495235
DOI:
10.1073/pnas.1621076114
[Indexed for MEDLINE]
Free PMC Article

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