Our work focuses on understanding how misfolded proteins are recognized and destroyed in the cell, how molecular chaperones mediate protein quality control “decisions”, how cellular stress impacts protein homeostasis ("proteostasis"), and how defects in protein architecture can be corrected. Our early work contributed to the discovery of the endoplasmic reticulum associated degradation (ERAD) pathway, which we named, and ongoing studies are deciphering the mechanisms underlying this pathway in yeast, mammalian cell culture, and rodent models. The importance of ERAD is evidenced by the fact that >70 human diseases are associated with the pathway, and numerous ERAD substrates play vital roles in human physiology. To determine the molecular basis of these diseases and other protein conformational diseases, we express specific protein substrates in yeast, tissue culture, and rodent models, and characterize factors mediating their folding and disposal--and concomitant stress responses--using genetic, biochemical, cellular, and pharmacological tools. In parallel, biochemical assays are being developed in which distinct steps during ERAD and protein biogenesis can be reconstituted. New classes of small molecule modulators of chaperones and the ubiquitin-proteasome pathway have also been isolated and show efficacy in a range of disease models.
