ER Protein Folding and Degradation

In eukaryotes, approximately 30% of all newly synthesized proteins pass through the endoplasmic reticulum (ER), where they undergo folding and maturation. A significant fraction of nascent proteins may fail to fold properly, which if not cleared efficiently may contribute to disease pathogenesis. These misfolded proteins in the ER are disposed of by a quality-control process known as ER-associated degradation (ERAD). ERAD is the first line of defense to recruit and retrotranslocate misfolded ER proteins for cytosolic proteasomal degradation. ERAD helps maintain a favorable folding environment for wildtype ER proteins, and has been implicated in over 70 human diseases. The long-term goal of our research program is to gain a comprehensive understanding of the cellular and physiological functions of mammalian ERAD.

 

Inflammation and Metabolism

Low-grade inflammation is shown to play a causal role in obesity-associated insulin resistance, type 2 diabetes, and other complications. However, how the inflammation and innate immunity crosstalk with metabolic processes to regulate metabolism remains poorly understood. We are interested in the role of Toll-like receptor (TLR) signaling pathways in regulating metabolism. TLR2 and TLR4 are key regulators of innate immunity against various pathogens. We recently showed that TLR2 and TLR4 also regulate pancreatic β cell proliferation, thus play a key role in the pathogenesis of diabetes. We are interested in further delineating how TLR-mediated inflammation is initiated and how the inflammatory signals control β cell proliferation in obesity and diabetes.