Co-chaperone CHIP promotes aggregation of ataxin-1.
Recent studies demonstrated that co-chaperone/E3 ligase CHIP (C-terminus of hsp70-interacting protein) mediates the ubiquitylation and suppresses the aggregation of polyglutamine (polyQ) proteins, such as huntingtin or ataxin-3. In this study, we investigated the effects of CHIP on the degradation of another polyQ protein ataxin-1. Interestingly CHIP associates not only with the polyQ-expanded ataxin-1 but also with the normal ataxin-1. Moreover, by enhancing ataxin-1 ubiquitylation, CHIP over-expression leads to a reduction in the solubility of ataxin-1 and thus increases the aggregate formation, especially that of polyQ-expanded ataxin-1. Domain analysis revealed that the TPR domain is required for the promotion of aggregation. By contrast, other co-chaperones or E3 ligases, such as BAG-1 or parkin, did not show similar effects on the aggregation of ataxin-1. Importantly, the effect of CHIP is impaired by the mutation of Ser776 of ataxin-1 whose phosphorylation is crucial for ataxin-1 aggregation. Our findings suggest that the role of CHIP in aggregation of polyQ proteins greatly varies depending on the context of full-length polyQ proteins.
Choi
Jung Young
JY
Protein Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, South Korea.
Ryu
Jeong Hee
JH
Kim
Hyo-Sun
HS
Park
Sung Goo
SG
Bae
Kwang-Hee
KH
Kang
Sunghyun
S
Myung
Pyung Keun
PK
Cho
Sayeon
S
Park
Byoung Chul
BC
Lee
Do Hee
DH
D000595:Amino Acid Sequence / Q000235:genetics; D000067696:Ataxin-1; D000067528:Ataxins; D002460:Cell Line; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D025801:Ubiquitin; C097188:polyglutamine; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases