Our laboratory is interested in understanding cellular mechanisms that prevent accumulation and aggregation of misfolded proteins in the cell. A better understanding of these mechanisms is essential for developing effective treatments for numerous human disorders including diabetes, neurodegeneration, and aging. We are specifically interested in the endoplasmic reticulum (ER) associated pathways that play a central role in preventing accumulation of misfolded proteins. The ER is the major site for synthesis, folding and maturation of secretory and membrane proteins, which account for nearly one third of the human proteome. Folding of these proteins is aided by chaperones and enzymes in the lumen of the ER. Despite this support, a significant proportion of newly synthesized proteins are misfolded in the ER due to genetic mutations, complexity of folding, and changes in the flux of proteins. Thus, the ER has evolved with two important pathways to deal with these misfolded proteins:
- The unfolded protein response (UPR) pathway senses the misfolded proteins in the ER and induces the genes responsible for increasing ER folding capacity.
- The ER associated degradation (ERAD) pathway routes the misfolded proteins from the ER to the cytosol for degradation by the proteasome.
We use a variety of techniques, including biochemical reconstitution, mammalian cell culture, molecular biology and cell imaging to understand molecular mechanisms involved in these pathways.