Abstract
To maintain quality control in cells, mechanisms distinguish among improperly folded peptides, mature and functional proteins, and proteins to be targeted for degradation. The molecular chaperones, including heat-shock protein Hsp90, have the ability to recognize misfolded proteins and assist in their conversion to a functional conformation. Disruption of Hsp90 heterocomplexes by the Hsp90 inhibitor geldanamycin leads to substrate degradation through the ubiquitin–proteasome pathway1,2,3, implicating this system in protein triage decisions. We previously identified CHIP (carboxyl terminus of Hsc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). CHIP also interacts directly with a tetratricopeptide repeat acceptor site of Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate5, even though it has little effect on its synthesis. Instead, CHIP induces ubiquitylation of the glucocorticoid receptor and degradation through the proteasome. By remodelling Hsp90 heterocomplexes to favour substrate degradation, CHIP modulates protein triage decisions that regulate the balance between protein folding and degradation for chaperone substrates.
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Acknowledgements
The authors thank D. Toft, E. B. Thompson and F. U. Hartl for generous provision of reagents. This work was supported by the NIH (C.P) and by the Deutsche Forschung gemeinschaft.
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Department of Molecular Cell Biology, Max-Planck-Institute for Biochemistry, Martinsried, Germany
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Figure S1
Molecular interactions between CHIP and Hsp90. a. COS-7 cells were immunoprecipitated with 3G3 or a control antibody (NS) and analysed by western blotting with anti-CHIP antiserum. b. Human skeletal muscle cell lysates were immunoprecipitated (IP) with anti-CHIP or preimmune serum and analyzed by Western blotting with AC88 to detect Hsp90. c. Binding assays were performed with Hsp90 or Hsc70 and GST or GSTÐCHIP fusion proteins containing the amino-acid residues in brackets. Western blots were probed with anti-Hsp90 or anti-Hsc70 antibodies. AA, amino acids. d. Binding assays were performed using GST or GST fusion proteins of full-length CHIP with Hsc70 or increasing concentrations of Hsp90. Hsc70 bound to CHIP was visualized by western blotting. e. Binding assays were performed with recombinant CHIP and GST or GST fusion proteins containing the indicated amino-acid residues of Hsp90. f. CHIP was incubated with Hsp90(629Ð732) fused to GST in the absence or presence of equimolar or 10-fold molar excess of Hop. CHIP bound to Hsp90 was visualized by western blotting. (GIF 41 kb)
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Connell, P., Ballinger, C., Jiang, J. et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3, 93–96 (2001). https://doi.org/10.1038/35050618
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DOI: https://doi.org/10.1038/35050618
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