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p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.

Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and co-immunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

Pubmed ID: 16286508

Authors

  • Bjørkøy G
  • Lamark T
  • Brech A
  • Outzen H
  • Perander M
  • Overvatn A
  • Stenmark H
  • Johansen T

Journal

The Journal of cell biology

Publication Data

November 21, 2005

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Autophagy
  • Cell Death
  • Cell Line, Tumor
  • Cell Membrane
  • Cell Movement
  • Cell Nucleus
  • Cell Survival
  • Cytoplasm
  • Cytosol
  • Detergents
  • Green Fluorescent Proteins
  • HeLa Cells
  • Heat-Shock Proteins
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lysosomes
  • Mice
  • Microscopy, Confocal
  • Microscopy, Electron
  • Microscopy, Video
  • Microtubule-Associated Proteins
  • Models, Biological
  • Models, Genetic
  • Mutation
  • NIH 3T3 Cells
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Plasmids
  • Polymers
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins
  • Transfection
  • Ubiquitin