Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates.
A hallmark of most neurodegenerative diseases, including those caused by polyglutamine expansion, is the formation of ubiquitin (Ub)-positive protein aggregates in affected neurons. This finding suggests that the Ub system may be involved in common mechanisms underlying these otherwise unrelated diseases. Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the neurodegenerative disease spinocerebellar ataxia type 3, in a bioinformatics search of the human genome for components of the Ub system. We show that wild-type Atx-3 is a Ub-binding protein and that the interaction of Atx-3 with Ub is mediated by motifs homologous to those found in a proteasome subunit. Both wild-type Atx-3 and the otherwise unrelated Ub-binding protein p62/Sequestosome-1 have been shown to be sequestered into aggregates in affected neurons in several neurodegenerative diseases, but the mechanism for this recruitment has remained unclear. In this article, we show that functional Ub-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates in a cell-based assay that recapitulates several features of polyglutamine disease. We propose that the Ub-mediated sequestration of essential Ub-binding protein(s) into aggregates may be a common mechanism contributing to the pathogenesis of neurodegenerative diseases.
Donaldson
Kathryn M
KM
Department of Cancer and Cell Biology, Genomics Institute of the Novartis Research Foundation (GNF), 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
Li
Wei
W
Ching
Keith A
KA
Batalov
Serge
S
Tsai
Chih-Cheng
CC
Joazeiro
Claudio A P
CA
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000067699:Ataxin-3; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D000071456:Sequestosome-1 Protein; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017874:Immediate-Early Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex