Department of Pharmacology, University of Virginia
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.
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​We integrate physiology and biochemistry with cell biology and genetics to dissect the molecular processes of ERAD in the context of protein misfolding diseases, thereby producing exciting new insights into disease pathogenesis and treatment. Our major research directions include:
1. The role of ERAD in liver physiology, protein conformational diseases, and lipid metabolism:
Many diseases are now recognized as 'conformational diseases,' caused by protein misfolding and subsequent aggregation. Our research aims to understand the significance of ERAD in protein biogenesis and nutrient metabolism in the liver. We focus on investigating how ERAD mediates the quality control of proteins associated with various human conformational diseases. Additionally, we explore how ERAD regulates lipid metabolism in the context of obesity, hyperlipidemia, and cardiovascular diseases. We use various transgenic and disease mouse models, biochemical tools, primary cell culture, and proteomics approaches in these studies.
Hepatic fibrinogen storage disease (HFSD) is a protein conformational disorder characterized by the retention and aggregation of fibrinogen, a crucial blood coagulation factor. SEL1L-HRD1 ERAD deficiency in hepatocytes leads to the formation of inclusion bodies in the liver (arrows), mimicking HFSD in humans. Subsequent mechanistic studies reveal the critical role of ERAD in the biogenesis and quality control of fibrinogen. (Song et al. Nat Commun. 2024. Under revision.)
2. The role of ERAD in iron metabolism:
Our research aims to understand how ERAD regulates iron homeostasis both under physiological conditions and in disease states. Iron metabolism is crucial for cellular and organismal growth and must be tightly regulated to prevent toxicity from excess or anemia from deficiency. We study how ERAD influences iron balance through various transporters and hormones in normal conditions and how it affects disease-causing protein variants in pathological conditions. We use novel transgenic mouse models and advanced cell biology techniques to address these questions.
SEL1L-HRD1 ERAD in hepatocytes controls systemic iron homeostasis by regulating the turnover of both WT and disease mutant CP proteins under physiological and pathological conditions, respectively. (Thepsuwan, et al. PNAS. 2023.)
3. The role of ERAD in germline stem cell differentiation:
Germline stem cell differentiation, essential for reproduction, demands precise regulation of cellular functions and protein homeostasis. This process involves the generation of various secretory and membrane proteins in the ER as structural and signaling molecules, requiring stringent modulation of ER homeostasis. However, the underlying molecular mechanisms remain poorly understood. Our research aims to elucidate the importance of ERAD in maintaining the proper differentiation of germline stem cells, such as during spermatogenesis. We use state-of-the-art ultrastructural imaging techniques and various in vivo tools in these studies.
Schematic illustration highlighting the dramatic cellular morphological changes and organelle dynamics during spermatogenesis. (Santen, R. J. and R. S. Swerdloff. 1986. Marcel Dekker.)