Tissue-specifity of Hsp90 chaperone networks

Molecular chaperones are essential proteins that prevent misfolding, facilitate folding to the native state, and regulate the assembly and disassembly of macromolecular complexes. Hsp90 is a core component of the molecular chaperone network based on its essential roles in a wide range of cellular processes including cell cycle, signal transduction, development, transcription, and protein refolding after stress conditions. The functions of Hsp90 and its regulatory co-chaperones have been studied extensively in a variety of prokaryotic and eukaryotic organisms at the biochemical and cellular levels. However, very little is understood at the organismal level how the physiological roles of the Hsp90 chaperone network integrate among tissues to affect development and ageing. Genetic observations from plants and mice suggest tissue-specific requirements for different components of the Hsp90 network. Moreover, high-throughput gene expression profiling studies in C. elegans indicate tissue-specific expression patterns for Hsp90 itself and its co-chaperones. Since different Hsp90 substrates require different combinations of Hsp90 co-chaperone components, the Hsp90 chaperone network may be tissue-specific in multi- cellular organisms. To address that question, I will examine the functional requirements and expression patterns for Hsp90 and its co-chaperone network (Hsp90 chaperome) in the nematode C. elegans. I will approach this by determining the Hsp90 chaperome requirements for the endogenous substrates DAF-11, a transmembrane guanylyl cyclase expressed in chemosensory neurons, and UNC-54, the major isoforms of type II myosin heavy chain that is specifically expressed in the body wall muscle cells. These functional studies will be complemented by expression pattern analysis of Hsp90 chaperome components to establish their expression pattern during development and ageing. Moreover, I will determine alterations in the neuron- and muscle-specific folding capacity of the Hsp90 chaperome at the presence of chronic proteotoxic stress, as induced via the expression of disease-related aggregation prone proteins in neurons and muscles. C. elegans with comprehensive genetic tools and databases as well as transparency and short lifespan offers many advantages to uncover physiological roles of the Hsp90 chaperome at the level of the multi-cellular organism.