ARHGEF2 isoform switching couples intestinal epithelial barrier function with autophagic host defense response to pathogens
7 affiliations
- 1Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas USA
- 2Department of Immunology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas USA
- 3Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health University of Texas Southwestern Medical Center, Dallas, Texas USA
- 4Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX USA
- 5Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX USA
- 6Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas USA
- 7Simmons Cancer Center, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas USA
Abstract
Intestinal epithelial integrity is essential for host defense, yet how epithelial junctional scaffolds coordinate antimicrobial immunity remains unclear. We show that the long GEF-H1 isoforms (mouse Arhgef2-207; human ARHGEF2-219) localize to adherens junctions in polarized epithelial cells through interactions with actin and Nectin-3, whereas the shorter Arhgef2-201 isoform localizes to tight junctions. Conditional deletion of epithelial Arhgef2-207 induces Arhgef2-201 expression, disrupts barrier integrity, activates autophagy, and causes small-intestinal inflammation. In human intestinal organoids, Listeria monocytogenes selectively depletes junction-associated ARHGEF2-219, triggering a switch to ARHGEF2-201 and RhoA- and STING-mediated autophagic signaling. This transition coincides with loss of the Na⁺/K⁺-ATPase and epithelial polarity. Here we show that a pathogen-induced ARHGEF2 isoform switch links junctional perturbation to autophagic responses and immune activation, revealing a mechanism that couples barrier disruption to cell-intrinsic antimicrobial defense.
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BibTeX
@article{chen2026arhgef2,
title = {{ARHGEF2 isoform switching couples intestinal epithelial barrier function with autophagic host defense response to pathogens}},
author = {Shuyuan Chen and Alka Diwaker and Xi Li and Abdulmajeed Salamah and Lei Guo and Neethu S. Alex and Ashutosh Shukla and Mary-Joe Touma and Yassin EL-Najjar and Lin Xu and Jianyi Yin and Ezra Burstein and Marcel Mettlen and Andrew Lemoff and Suraj Patel and Josephine Ni and Hans-Christian Reinecker},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-78030-w},
url = {https://doi.org/10.1038/s41467-026-78030-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ARHGEF2 isoform switching couples intestinal epithelial barrier function with autophagic host defense response to pathogens
AU - Shuyuan Chen
AU - Alka Diwaker
AU - Xi Li
AU - Abdulmajeed Salamah
AU - Lei Guo
AU - Neethu S. Alex
AU - Ashutosh Shukla
AU - Mary-Joe Touma
AU - Yassin EL-Najjar
AU - Lin Xu
AU - Jianyi Yin
AU - Ezra Burstein
AU - Marcel Mettlen
AU - Andrew Lemoff
AU - Suraj Patel
AU - Josephine Ni
AU - Hans-Christian Reinecker
PY - 2026
DA - 2026/09/24
JO - Nature Communications
DO - 10.1038/s41467-026-78030-w
UR - https://doi.org/10.1038/s41467-026-78030-w
AB - Intestinal epithelial integrity is essential for host defense, yet how epithelial junctional scaffolds coordinate antimicrobial immunity remains unclear. We show that the long GEF-H1 isoforms (mouse Arhgef2-207; human ARHGEF2-219) localize to adherens junctions in polarized epithelial cells through interactions with actin and Nectin-3, whereas the shorter Arhgef2-201 isoform localizes to tight junctions. Conditional deletion of epithelial Arhgef2-207 induces Arhgef2-201 expression, disrupts barrier integrity, activates autophagy, and causes small-intestinal inflammation. In human intestinal organoids, Listeria monocytogenes selectively depletes junction-associated ARHGEF2-219, triggering a switch to ARHGEF2-201 and RhoA- and STING-mediated autophagic signaling. This transition coincides with loss of the Na⁺/K⁺-ATPase and epithelial polarity. Here we show that a pathogen-induced ARHGEF2 isoform switch links junctional perturbation to autophagic responses and immune activation, revealing a mechanism that couples barrier disruption to cell-intrinsic antimicrobial defense.
SN - 2041-1723
ER -