Title |
Ubiquitin-specific protease 14 regulates c-Jun N-terminal kinase signaling at the neuromuscular junction
|
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Published in |
Molecular Neurodegeneration, January 2015
|
DOI | 10.1186/1750-1326-10-3 |
Pubmed ID | |
Authors |
Jada H Vaden, Bula J Bhattacharyya, Ping-Chung Chen, Jennifer A Watson, Andrea G Marshall, Scott E Phillips, Julie A Wilson, Gwendalyn D King, Richard J Miller, Scott M Wilson |
Abstract |
Ubiquitin-specific protease 14 (USP14) is one of three proteasome-associated deubiquitinating enzymes that remove ubiquitin from proteasomal substrates prior to their degradation. In vitro evidence suggests that inhibiting USP14's catalytic activity alters the turnover of ubiquitinated proteins by the proteasome, although whether protein degradation is accelerated or delayed seems to be cell-type and substrate specific. For example, combined inhibition of USP14 and the proteasomal deubiquitinating enzyme UCH37 halts protein degradation and promotes apoptosis in multiple myeloma cells, whereas USP14 inhibition alone accelerates the degradation of aggregate-prone proteins in immortalized cell lines. These findings have prompted interest in USP14 as a therapeutic target both inside and outside of the nervous system. However, loss of USP14 in the spontaneously occurring ataxia mouse mutant leads to a dramatic neuromuscular phenotype and early perinatal lethality, suggesting that USP14 inhibition may have adverse consequences in the nervous system. We therefore expressed a catalytically inactive USP14 mutant in the mouse nervous system to determine whether USP14's catalytic activity is required for neuromuscular junction (NMJ) structure and function. |
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