Protein Degradation and Cholesterol Regulation

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HMG-CoA reductase (HMGR) is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. Regulated degradation of HMGR allows control of the levels of this enzyme in response to changing cellular need for cholesterol pathway products. Although untapped as an axis of clinical modulation, the regulated degradation of HMGR is absolutely specific for HMGR and thus holds promise for devising new strategies for modulation. Furthermore, HMGR is degraded by a poorly-understood pathway of degradation called ER-associated degradation (ERAD), a process that is implicated in management of cellular stress and in the regulation of numerous other medically important proteins. The investigator is studying the conserved mechanisms by which HMGR undergoes regulated degradation, using yeast molecular biology, biochemistry, and forward and reverse genetics to reveal the underlying mechanisms. The work has shown that the ubiquitin proteasome pathway is central to the regulated degradation of HMGR, a mechanism in operation for mammalian HMGR as well. The current goals are to discover all the proteins responsible for regulated degradation, by the isolation and study of HRD genes (Hmg co a Reductase Degradation), that encode the degradation machinery of ERAD, and COD genes (Control Of reductase Degradation), that encode proteins responsible for the coupling of the sterol pathway signals to the stability of HMGR. Current goals are 1) the analysis of discovered HRD and COD genes, 2) characterize the features of the HMGR molecule that allow it to undergo this unique mode of control; 3) develop and exploit methods to isolate new members of each gene class, and 4) reconstitute regulated degradation of HMGR in vitro using the tools and techniques derived from these efforts.