β-arrestin1–mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation

Gastrointestinal toxicity limits the clinical application of abdominal and pelvic radiotherapy and currently has no effective treatment. Intestinal leucine-rich-repeat-containing GPCR 5 (Lgr5)-positive stem cell depletion and loss of proliferative ability due to radiation may be the primary factors causing intestinal injury following radiation. Here, we report the critical role of β-arrestin1 (βarr1) in radiation-induced intestinal injury. Intestinal βarr1 was highly expressed in radiation enteritis and in a radiation model. βarr1 knockout (KO) or knockdown mice exhibited increased proliferation in intestinal Lgr5+ stem cell, crypt reproduction, and survival following radiation. Unexpectedly, the beneficial effects of βarr1 deficiency on intestinal stem cells in response to radiation were compromised when the endoplasmic reticulum stress-related protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α) pathway was inhibited, and this result was further supported in vitro. Furthermor...