Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo.
Deubiquitinases (DUBs) are proteases that regulate various cellular processes by controlling protein ubiquitination. Cell-based studies indicate that the regulation of the activity of DUBs is important for homeostasis and is achieved by multiple mechanisms, including through their own ubiquitination. However, the physiological significance of the ubiquitination of DUBs to their functions in vivo is unclear. Here, we report that ubiquitination of the DUB ataxin-3 at lysine residue 117, which markedly enhances its protease activity in vitro, is critical for its ability to suppress toxic protein-dependent degeneration in Drosophila melanogaster. Compared with ataxin-3 with only Lys-117 present, ataxin-3 that does not become ubiquitinated performs significantly less efficiently in suppressing or delaying the onset of toxic protein-dependent degeneration in flies. According to further studies, the C terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase that ubiquitinates ataxin-3 in vitro, is dispensable for its ubiquitination in vivo and is not required for the neuroprotective function of this DUB in Drosophila. Our work also suggests that ataxin-3 suppresses degeneration by regulating toxic protein aggregation rather than stability.
['Tsou|Wei-Ling|WL|', 'Burr|Aaron A|AA|', 'Ouyang|Michelle|M|', 'Blount|Jessica R|JR|', 'Scaglione|K Matthew|KM|', 'Todi|Sokol V|SV|']
D000818:Animals D000067699:Ataxin-3 D029721:Drosophila Proteins D004331:Drosophila melanogaster D018507:Gene Expression Regulation, Developmental D008239:Lysine D051379:Mice D018345:Mice, Knockout D009154:Mutation D009419:Nerve Tissue Proteins D009687:Nuclear Proteins D010858:Pigmentation D059748:Proteolysis D012097:Repressor Proteins D012160:Retina D025801:Ubiquitin D044767:Ubiquitin-Protein Ligases D064570:Ubiquitin-Specific Proteases D054875:Ubiquitination
Ubiquitin Neuroprotection Ataxin-3 Protease Drosophila Deubiquitination Machado-Joseph Disease Neurodegeneration Polyglutamine Disease