Reference Report

Reference
Citation	Al-Ramahi, I., Lam, Y.C., Chen, H.K., de Gouyon, B., Zhang, M., Perez, A.M., Branco, J., de Haro, M., Patterson, C., Zoghbi, H.Y., Botas, J. (2006). CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J. Biol. Chem. 281(36): 26714--26724. (Export to RIS)
FlyBase ID	FBrf0192832
Publication Type	Research paper
PubMed ID	16831871
PubMed Abstract	CHIP (C terminus of Hsc-70 interacting protein) is an E3 ligase that links the protein folding machinery with the ubiquitin-proteasome system and has been implicated in disorders characterized by protein misfolding and aggregation. Here we investigate the role of CHIP in protecting from ataxin-1-induced neurodegeneration. Ataxin-1 is a polyglutamine protein whose expansion causes spinocerebellar ataxia type-1 (SCA1) and triggers the formation of nuclear inclusions (NIs). We find that CHIP and ataxin-1 proteins directly interact and co-localize in NIs both in cell culture and SCA1 postmortem neurons. CHIP promotes ubiquitination of expanded ataxin-1 both in vitro and in cell culture. The Hsp70 chaperone increases CHIP-mediated ubiquitination of ataxin-1 in vitro, and the tetratricopeptide repeat domain, which mediates CHIP interactions with chaperones, is required for ataxin-1 ubitiquination in cell culture. Interestingly, CHIP also interacts with and ubiquitinates unexpanded ataxin-1. Overexpression of CHIP in a Drosophila model of SCA1 decreases the protein steady-state levels of both expanded and unexpanded ataxin-1 and suppresses their toxicity. Finally we investigate the ability of CHIP to protect against toxicity caused by expanded polyglutamine tracts in different protein contexts. We find that CHIP is not effective in suppressing the toxicity caused by a bare 127Q tract with only a short hemagglutinin tag, but it is very efficient in suppressing toxicity caused by a 128Q tract in the context of an N-terminal huntingtin backbone. These data underscore the importance of the protein framework for modulating the effects of polyglutamine-induced neurodegeneration.
DOI	10.1074/jbc.M601603200
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Language of Publication	English
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Publication Type	Journal
Abbreviation	J. Biol. Chem.
Title	Journal of Biological Chemistry
Publication Year	1905-
ISBN/ISSN	0021-9258
Data from Reference
Alleles (10)
	Avic\GFP^Scer\UAS.cUa Hsap\ATXN1^2Q.Scer\UAS Hsap\ATXN1^30Q.Scer\UAS Hsap\ATXN1^82Q.Scer\UAS Hsap\HTT^{NT.128Q.Scer\UAS} Hsap\STUB1^Scer\UAS.cAa Scer\GAL4^GMR.PF Scer\GAL4^ninaE.PT w^+mC Zzzz\CAG^{127Q.Scer\UAS.T:Ivir\HA1}
Constructs (9)
	P{GAL4-ninaE.GMR} P{rh1-GAL4} P{UAS-CHIP.A} P{UAS-GFP.U} P{UAS-Hsap\ATX1.30Q} P{UAS-Hsap\ATX1.82Q} P{UAS-HTT.NT.128Q} P{UAS-SCA1.2Q} P{UAS-Zzzz\CAG.127Q}
Genes (7)
	Avic\GFP Hsap\ATXN1 Hsap\HTT Hsap\STUB1 Scer\GAL4 w Zzzz\CAG
Natural transposons (1)
	P-element