Lysophosphatidic Acid Receptor Activation Regulates Expression of the Immediate Early Gene IEX-1 in Irradiated Cells and Tissues.

Immediate early response gene-3 (IER3/IEX-1) encodes a radiation-inducible stress-response adaptor protein that integrates pro-survival signaling pathways, yet the upstream mechanisms regulating its expression after irradiation remain incompletely understood. Here we investigated whether lysophosphatidic acid receptor (LPAR) signaling regulates IEX-1 expression during the radiation response and examined the radiobiological consequences of IEX-1 deficiency. LPAR activation enhanced IEX-1 expression in irradiated mouse whole blood, bone marrow, intestinal mucosa, and intestinal enteroids. In addition, IEX-1-deficient mice exhibited increased susceptibility to lethal radiation injury after total-body or partial body irradiation, while IEX-1-deficient enteroids displayed delayed growth and altered ERK phosphorylation kinetics. Together, these findings identify IEX-1 as a previously unrecognized downstream target of LPAR signaling after irradiation.