Chronic liver diseases are a major and growing public health problem in need of targeted therapies. Hepatocytes are responsible for the key functions of the liver, and are also the primary targets for toxic, inflammatory, metabolic, and other stresses. Our goal is to understand susceptibility factors in hepatocyte injury. Specifically, we are interested in the protein ecto-5'-nucleotidase (CD73), which is a major enzymatic source of extracellular adenosine and a mediator of mouse liver injury. We are investigating the regulation and function of CD73 and a novel splice variant that we identified (CD73S) in hepatocytes and liver injury models. By integrating studies in primary mouse and human hepatocytes, liver slices, liver-specific CD73-/- mice, and patient samples we seek to determine the biological mechanisms and potential of CD73 as a therapeutic target in alcoholic and non-alcoholic steatohepatitis.
CD73 is a complex molecule that undergoes N-glycosylation, disulfide bond-mediated homodimerization, and membrane association via a glycosylphosphatidylinositol (GPI) anchor. There is evidence that CD73 regulates cellular function independently of its enzymatic activity, but the non-enzymatic mechanisms have not been defined. We are testing the hypothesis that CD73 serves as a receptor to transmit signals across the cell membrane. Using high throughput ligand screens we identified several endogenous molecules as CD73 ligands in vitro, and are investigating the functional consequences of these interactions in hepatocytes.
Chronic liver diseases due to alcohol and other factors can progress to cirrhosis and hepatocellular carcinoma (HCC), the main type of liver cancer and major cause of cancer-related mortality worldwide. We found that NT5E, the gene that encodes CD73, undergoes alternative splicing in human cirrhosis and HCC to produce a novel splice variant (CD73S) which lacks enzymatic activity. In addition, glycosylation of the canonical CD73 isoform is significantly altered in HCC. We are investigating the isoform-dependent and glycosylation-mediated functions of CD73 in hepatocytes and HCC cells.
POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL CONTROL OF CD73 IN ADVANCED LIVER DISEASE
FUNCTION AND REGULATION OF CD73 DURING HEPATOCYTE STRESS AND LIVER INJURY
ENZYMATIC VERSUS NON-ENZYMATIC FUNCTIONS OF CD73 IN HEPATOCYTES
in the Cell Biology and Physiology Department at UNC-Chapel Hill