Congenital tufting enteropathy (CTE) is an early-onset severe intestinal disorder with the majority of individuals with CTE carrying mutations in EPCAM or SPINT2. Mice deficient in Spint2, encoding the protease inhibitor HAI-2, develop CTE-like intestinal failure, as a result of uninhibited activity of the serine protease matriptase leading to loss of EpCAM (epithelial cell adhesion molecule). Here, Roman Szabo and colleagues investigate the role of matriptase, HAI-2 and EpCAM in CTE pathogenesis. First, the authors show that loss of HAI-2 in mice leads to increased matriptase-mediated cleavage of EpCAM. Then, they generate mice that lack the matriptase cleavage site in EpCAM and observe that the cleavage-resistant EpCAM variants cannot rescue the intestinal phenotypes in Spint2-deficient mice. This suggests that EpCAM cleavage is not the main cause for the loss of HAI-2 intestinal phenotype. Additionally, the authors find that genetically inactivating matriptase can prevent intestinal defects in Spint2-deficient, cleavage-resistant EpCAM mice, indicating that matriptase does not drive intestinal dysfunction by excessive cleavage of EpCAM. Finally, mice expressing cleavage-resistant EpCAM develop late-onset intestinal defects and have shorter life span even in the presence of HAI-2, suggesting that EpCAM cleavage is required for proper intestinal function. Overall, this study provides new insights into EpCAM and CTE disease progression.
