title: Carboxyl-terminus of Hsc70 interacting protein mediates 2,5-hexanedione-induced neurofilament medium chain degradation.
abstract: 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.
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.forename: Fuyong
authors.initials: F
authors.lastname: Song
authors.forename: Cuili
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Sufang
authors.initials: S
authors.lastname: Yu
authors.forename: Keqin
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D057809:HEK293 Cells; D006588:Hexanones / Q000633:toxicity*; D006801:Humans; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D006588:Hexanones; D016900:Neurofilament Proteins; D010446:Peptide Fragments; C061195:neurofilament protein M; C011269:2,5-hexanedione; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases