title: Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology.
abstract: Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Ai-Xin
authors.initials: AX
authors.lastname: Song
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Hu
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000067699:Ataxin-3; D018797:Cell Cycle Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D025801:Ubiquitin / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D025801:Ubiquitin; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein