Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes.
A major hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. But, how the polyglutamine proteins are ubiquitinated and degraded by the proteasomes are not known. Here, we demonstrate that CHIP (C terminus of Hsp70-interacting protein) co-immunoprecipitates with the polyglutamine-expanded huntingtin or ataxin-3 and associates with their aggregates. Transient overexpression of CHIP increases the ubiquitination and the rate of degradation of polyglutamine-expanded huntingtin or ataxin-3. Finally, we show that overexpression of CHIP suppresses the aggregation and cell death mediated by expanded polyglutamine proteins and the suppressive effect is more prominent when CHIP is overexpressed along with Hsc70.
Jana
Nihar Ranjan
NR
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122-050, India. nihar@nbrc.ac.in
Dikshit
Priyanka
P
Goswami
Anand
A
Kotliarova
Svetlana
S
Murata
Shigeo
S
Tanaka
Keiji
K
Nukina
Nobuyuki
N
D000818:Animals; D017209:Apoptosis; D000067699:Ataxin-3; D002460:Cell Line; D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D017510:Protein Folding; D012097:Repressor Proteins; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
C108740:Chi protein, Drosophila; D029721:Drosophila Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D025801:Ubiquitin; C097188:polyglutamine; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D046988:Proteasome Endopeptidase Complex