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PMID: 16286508 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of cell biology ·Vol. 171 ·No. 4 ·2005-11-21 ·Pages 603-14

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

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism,physiology Animals Autophagy Cell Death Cell Line, Tumor Cell Membrane/metabolism Cell Movement Cell Nucleus/metabolism Cell Survival Cytoplasm/metabolism Cytosol/metabolism Detergents/pharmacology Green Fluorescent Proteins/chemistry HeLa Cells Heat-Shock Proteins/metabolism,physiology Humans Huntingtin Protein Immunoblotting Immunoprecipitation Lysosomes/chemistry Mice Microscopy, Confocal Microscopy, Electron Microscopy, Video Microtubule-Associated Proteins/physiology Models, Biological Models, Genetic Mutation NIH 3T3 Cells Nerve Tissue Proteins/metabolism,physiology Nuclear Proteins/metabolism,physiology Plasmids/metabolism Polymers/chemistry Protein Binding Protein Structure, Tertiary Proteins/metabolism,physiology Sequestosome-1 Protein Transfection Ubiquitin/chemistry
Chemicals
Adaptor Proteins, Signal Transducing Detergents Heat-Shock Proteins Htt protein, mouse Huntingtin Protein MAP1LC3A protein, human Microtubule-Associated Proteins Nerve Tissue Proteins Nuclear Proteins Polymers Proteins SQSTM1 protein, human Sequestosome-1 Protein Sqstm1 protein, mouse Ubiquitin Green Fluorescent Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Bjørkøy Geir
Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway.
Lamark Trond
Brech Andreas
Outzen Heidi
Perander Maria
Overvatn Aud
Stenmark Harald
Johansen Terje
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200507002
Published
2005-11-21
Epub
2005-00-14
Pages
603-14
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2171557
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200507002 PMC Full Text View journal details
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