Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes.
Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and ... degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70-CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Animals, DNA-Binding Proteins, Gene Expression, Green Fluorescent Proteins, HEK293 Cells, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Leupeptins, Mice, Mutagenesis, Site-Directed, Proteasome Endopeptidase Complex, Protein Binding, Protein Folding, Protein Transport, Proteolysis, Recombinant Fusion Proteins, Serum Albumin, Bovine, Transcription Factors, Ubiquitin-Protein Ligases
Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Animals, DNA-Binding Proteins, Gene Expression, Green Fluorescent Proteins, HEK293 Cells, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Leupeptins, Mice, Mutagenesis, Site-Directed, Proteasome Endopeptidase Complex, Protein Binding, Protein Folding, Protein Transport, Proteolysis, Recombinant Fusion Proteins, Serum Albumin, Bovine, Transcription Factors, Ubiquitin-Protein Ligases
Mol. Biol. Cell
Date: Sep. 01, 2011
PubMed ID: 21775628
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