The G-protein Coupled Receptor OXER1 is a Tissue Redox Sensor Essential for Intestinal Epithelial Barrier Integrity

Hunter College of the City University of New York
Department of Biological Sciences
Spring 2025 Inga Richter Seminar Series

Miklos Lengyel, MD, PhD
MSKCC

The G-protein coupled receptor OXER1 is a tissue redox sensor essential for intestinal epithelial barrier integrity

Reactive oxygen species (ROS) mediate mucosal barrier defense but can also mutagenize and damage healthy host tissue that lacks proper protection. Because ROS dependent bystander damage contributes to asthma, ulcerative colitis, and cancer, it is an important therapeutic target. ROS stimulate the production of arachidonic acid metabolite 5-KETE. Through its receptor OXER1, 5-KETE promotes rapid leukocyte recruitment to damage and infection sites in fish and primates. As the popular rodent models lack obvious OXER1 orthologs, research into potential adaptive functions of this ROS-sensitive pathway is lacking. Here, we show that the OXER1 pathway mediates mucosal adaptation to oxidative stress in zebrafish and human cells. Loss of the OXER1 ortholog hcar1-4 causes barrier permeability and chronic infection by promoting epithelial apoptosis in the zebrafish intestine. Likewise, OXER1 protects human intestinal epithelial cells from oxidative nucleotide lesions and apoptosis. To this end, OXER1 induces NUDIX hydrolases that catabolize oxidized nucleotides like 8-oxoG, bolstering ROS
resilience without compromising ROS dependent immune defense. Loss of this mechanism can lead to increased mutagenesis, raising the hypothesis that OXER1 is a new tumor suppressor protein. We propose that this mechanism may be therapeutically harnessed to protect mucosal linings from damage, infection, and mutagenesis.