title: β-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury.
abstract: Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that β-arrestin-2 (βarr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. βArr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from βarr2-deficient mice depended on prolonged nuclear factor-κB (NF-κB) activation via direct interaction of βarr2 with IκBα and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, βarr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, βarr2 knockdown also provided significant radioresistance by manipulating NF-κB/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the βarr2/NF-κB/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. βArrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that β-arrestin-2 (βarr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, βarr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-κB activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. βArr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D045325:HCT116 Cells; D006801:Humans; D007422:Intestines / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D034622:RNA Interference; D011839:Radiation, Ionizing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D013450:Sulfones / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D051017:Apoptosis Regulatory Proteins; C493597:Lgr5 protein, mouse; D016328:NF-kappa B; D009570:Nitriles; C488588:PUMA protein, mouse; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000071560:beta-Arrestin 2; D000072000:NF-KappaB Inhibitor alpha