[
International Worm Meeting,
2003]
Protein folding homeostasis is a prerequisite for cell survival and involves molecular chaperones and the proteasome, which function in the folding and degradation machineries, respectively. Little is known about how these two systems communicate with each other, but the carboxy-terminus of Hsp70-interacting protein (CHIP) was recently identified as a protein that interacts with both molecular chaperones and the ubiquitin-proteasome pathway. Human CHIP binds to Hsp70 and Hsp90 through its tetratricopeptide repeat domain and negatively regulates the folding activity of both chaperones. In addition to being a co-chaperone, CHIP is a U-box type E3 ubiquitin ligase and interacts with the proteasome, thus providing a potential molecular link between folding and degradation pathways. However, the biological role of CHIP in a multicellular organism is poorly understood. We are using C. elegans to characterize the function of CHIP in development and survival upon stress conditions. We have identified a C. elegans CHIP homolog that shows 40% identity and 59% similarity with the human protein. Currently, we are conducting biochemical studies to establish whether CeCHIP possesses functional properties similar to its human homolog, as well as studies to establish the tissue expression pattern of CeCHIP. N2s grown on Cechip RNAi bacteria showed no gross phenotype, suggesting that CeCHIP is not essential for the development of the worm. Given that mammalian CHIP interacts with both the folding and the degradation machineries, we hypothesize that changes in the expression level of CeCHIP should have profound consequences on the worms capacity to cope with stress conditions. To address this question, we are examining the worms response to various stresses, such as heat and exogenous expression of aggregation-prone proteins in the context of Cechip over-expression or RNAi. Taken together, these studies should reveal new insights into the biological function of CHIP in maintaining protein homeostasis in a multicellular organism.