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

## TL;DR

This study reveals how a protein isoform switch in intestinal cells connects tissue barrier function to autophagy, a key defense mechanism against pathogens.

## Contribution

The paper identifies a novel pathway linking junctional perturbation to autophagy and immune activation via ARHGEF2 isoform switching.

## Key findings

- Conditional deletion of Arhgef2-207 in intestinal epithelium causes barrier loss, autophagy activation, and inflammation.
- Infection with Listeria monocytogenes triggers an ARHGEF2 isoform switch, inducing autophagy through STING and LC3.
- The isoform switch correlates with loss of Na+/K+-ATPase and epithelial polarity.

## Abstract

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. In human intestinal organoids, infection with Listeria monocytogenes selectively targets the junction-associated ARHGEF2–219 isoform, triggering an isoform switch to ARHGEF2-201 and induction of autophagy through interaction with STING and LC3. This transition coincides with a loss of Na+/K+-ATPase and epithelial polarity. Together, these findings identify a pathogen-induced ARHGEF2 isoform switch that links junctional perturbation to autophagy and mucosal immune activation, defining a previously unrecognized pathway by which epithelial cells couple barrier disruption to cell-intrinsic host defence.