Carboxyl-terminus of Hsc70 interacting protein mediates 2,5-hexanedione-induced neurofilament medium chain degradation

Neurofilaments (NFs), the most abundant cytoskeletal components in large neurons and myelinated axons, are the targets of n-hexane-induced neuropathy, in which a specific loss of NFs protein has been frequently observed. However, the precise mechanisms regulating NFs contents are not well understood...

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Bibliographic Details
Published in:Biochemical pharmacology 2011-03, Vol.81 (6), p.793-799
Main Authors: Wang, Qingshan, Song, Fuyong, Zhang, Cuili, Zhao, Xiulan, Zhu, Zhenping, Yu, Sufang, Xie, Keqin
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Axon guidance
axons
Biological and medical sciences
Cells, Cultured
Cytoskeleton
Enzymes
HEK293 Cells
Hexanones - toxicity
Hsc70 protein
Humans
Male
Medical sciences
n-Hexane
nerve tissue
Neurofilament Proteins - metabolism
Neurofilaments
Neurons
Neuropathy
Neurotoxicity
Peptide Fragments - physiology
peripheral nervous system diseases
pharmacology
Pharmacology. Drug treatments
proteasome endopeptidase complex
proteasome inhibitors
proteasomes
Proteolysis
Rats
Rats, Wistar
Sciatic nerve
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - physiology
ubiquitination
Ubiquitin–proteasome system
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Summary:Neurofilaments (NFs), the most abundant cytoskeletal components in large neurons and myelinated axons, are the targets of n-hexane-induced neuropathy, in which a specific loss of NFs protein has been frequently observed. However, the precise mechanisms regulating NFs contents are not well understood. The aim of this study was to elucidate the role of ubiquitin–proteasome system (UPS) in NFs degradation. We first demonstrated that the E3 ligase carboxyl-terminus of Hsc70 interacting protein (CHIP), originally identified as a co-chaperone of Hsc70, directly interacted with NFs medium chain (NF-M) and then enhanced NF-M ubiquitination and degradation after 2,5-hexanedione (HD) treatment. Consistent with this result, the application of proteasome inhibitor MG132 partly reversed HD-induced decrease of NF-M. Finally, we found that other components of UPS system (e.g. ubiquitin-activating enzyme E1, CHIP and proteasome) were significantly increased in sciatic nerve of HD-intoxicated rats. In conclusion, this study indicated that the CHIP ubiquitin ligase complex interacted with and repressed NFs by targeting NFs for ubiquitin-mediated proteolysis, which led to reduction of NFs contents in HD-induced neuropathy.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2010.12.021