Molecular chaperones participate in the folding, maturation, and proper subcellular targeting of nascent proteins or, conversely, the recovery of function of proteins that have been misfolded or otherwise damaged by cellular stressors. However, chaperones participate in a variety of processes that seem related to protein folding only indirectly, or not at all. At the same time, it is becoming increasingly apparent that molecular chaperones do not represent the sum total of the cell stress response, and that a range of events other than protein refolding are required to maintain viability and protect the intracellular environment in adverse circumstances. We previously identified CHIP (carboxyl-terminus of Hsc70-/nteracting protein) in a screen for stress-responsive genes. We have since found that CHIP interacts with the chaperones Hsc70, Hsp70, and Hsp90 and has complex and coordinated effects on their functions. In addition, CHIP has ubiquitin ligase activity and plays a critical role in regulating protein quality control within the cytoplasm. Finally, we have recently found that CHIP activates heat shock factor 1 (HSF1) and thus directly coordinates the transcriptional stress response. We hypothesize that CHIP acts as a stress capacitor by linking the activities of different effector arms of the stress response. In particular, we hypothesize that CHIP regulates protein folding, transcriptional responses, protein quality control, and perhaps other events that occur during the stress response. By expanding our understanding of CHIP and taking advantage of the reagents and approaches we have developed, we are in an excellent position to revise and refine the present understanding of how cells response to stress under pathophysiologic conditions. To do this, we propose four aims:
Specific aim #1 - Examine the functional interaction between CHIP and HSF1.;
Specific aim #2 - Characterize the nuclear functions of CHIP;
Specific aim #3 - Determine how BAG2 modulates the activity of the CHIP ubiquitin ligase complex;
Specific aim #4 - Characterize the relationship between CHIP, heat shock proteins, and substrates in the protein triage network. These studies will help us to develop new models about the relationship between cytoplasmic quality control mechanisms and the cellular stress response. ? ?
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