Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates

Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8892-7. doi: 10.1073/pnas.1530212100. Epub 2003 Jul 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Ataxin-3
  • Binding Sites / genetics
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • In Vitro Techniques
  • Molecular Sequence Data
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Mutation
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Nuclear Proteins
  • Peptides / chemistry
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins
  • Sequence Homology, Amino Acid
  • Sequestosome-1 Protein
  • Transfection
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Immediate-Early Proteins
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Proteins
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex