ARHGEF2 Isoform Switching Couples Intestinal Epithelial Barrier Function with Autophagic Response to Pathogens

Maintenance of intestinal epithelial integrity is essential for host defence, yet how epithelial junctional scaffolds connect to antimicrobial autophagy remains unclear. Here we show that distinct isoforms of the guanine nucleotide exchange factor GEF-H1 (mouse Arhgef2-207; human ARHGEF2-219) localize to adherens junctions in polarized intestinal epithelial cells through interaction with the adhesion molecule Nectin-3 and the cytoskeletal scaffold Afadin. Conditional deletion of Arhgef2-207 in the intestinal epithelium induces compensatory expression of the shorter Arhgef2-201, leading to loss of barrier integrity, activation of autophagy, and small-intestinal inflammation. Overall design: Human organoids before and after 4 hour Listeria infection