title: CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation.
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.
authors.affiliation: Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.forename: Yung C
authors.initials: YC
authors.lastname: Lam
authors.forename: Hung-Kai
authors.initials: HK
authors.lastname: Chen
authors.forename: Beatrice
authors.initials: B
authors.lastname: de Gouyon
authors.forename: Minghang
authors.initials: M
authors.lastname: Zhang
authors.forename: Alma M
authors.initials: AM
authors.lastname: Pérez
authors.forename: Joana
authors.initials: J
authors.lastname: Branco
authors.forename: Maria
authors.initials: M
authors.lastname: de Haro
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000033:anatomy & histology; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010455:Peptides / Q000633:toxicity; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D017510:Protein Folding; D020754:Spinocerebellar Ataxias / Q000378:metabolism / Q000473:pathology; D019076:Transgenes; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: 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