The Lencer laboratory studies the cell and molecular biology of vesicular transport in polarized epithelial cells and regulation of ion transport in the intestine. These projects relate to how intestinal epithelial cells interact with the luminal and sub-epithelial microenvironment, and to the biology of bacterial pathogenesis and mucosal host defense.
In one project, we have discovered how the enteric bacterial toxin, cholera toxin (CT), breeches the intestinal epithelial barrier and enters host epithelial cells to cause disease. CT and the other AB5-subunit toxins hijack membrane lipids and the cellular and molecular mechanisms of retrograde membrane transport to move from the plasma membrane into the endoplasmic reticulum (ER) of affected cells. Once in the ER, a portion of the toxin, the A1-chain, co-opts components of ERAD (ER-associated degradation) to retro-translocate to the cytosol where it acts enzymatically to cause disease. The pathway from PM to ER and cytosol can be viewed in some ways as almost the total reverse of protein biosynthesis. We use cell-culture and biochemical model systems, and have recently defined the zebrafish as a genetic model for studies on toxin transport into the ER and retro-translocation to the cytosol. Both reverse and forward genetics are possible. Thirteen mutant fish resistant to intoxication have been identified by forward genetic screen.
In another project, we study how IgG is transported by the Fcγ-receptor FcRn across epithelial barriers to affect mucosal immunity and host defense. Here, the pathway taken by FcRn across the cell is bidirectional and avoids the late-endosome and lysosome. These studies are cell-culture based using gene-silencing driven by conditional promoters to examine the membrane biology that explains sorting of the receptor in this pathway.
In a third area of interest, we aim to understand the regulation of Cl- secretion and water transport in the intestine. These studies address the biology of several ion transporters responsible for secretory diarrhea.