title: β-Arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis.
abstract: β-Arrestins (β-arrs) are regulators and mediators of G protein-coupled receptor signaling, and accumulating evidence suggests that they are functionally involved in inflammation and autoimmune diseases. However, the effect of β-arrs is unclear in inflammatory bowel disease (IBD), and the role of β-arr2 is unknown in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study is to investigate whether β-arr2 encourages inflammation-induced epithelial apoptosis through endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) in colitis. In the present study, the results showed that β-arr2 was increased in specimens from patients with UC or CD. Furthermore, a β-arr2 deficiency significantly repressed intestinal inflammation, ameliorated colitis, and alleviated mucosal apoptosis in mice. In addition, the targeted deletion of β-arr2 depressed ER stress, inhibited PUMA, and downregulated PUMA-mediated mitochondrial apoptotic signaling in colitis. β-Arr2, an important modulator of G protein-coupled receptor function, binds eIF2α to activate ER stress signaling. Furthermore, the knockdown of PUMA dramatically prevented β-arr2-induced apoptosis via alleviating ER stress in vitro. The results suggest that β-arr2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis and that β-arr2 is a potential therapeutic target for colitis.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: L X
authors.initials: LX
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: S W
authors.initials: SW
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Y D
authors.initials: YD
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Liu
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: B
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000276:immunology; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D000069285:Infliximab / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D051017:Apoptosis Regulatory Proteins; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C438378:BBC3 protein, human; D015852:Eukaryotic Initiation Factor-2; D005765:Gastrointestinal Agents; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016264:Dextran Sulfate; D000069285:Infliximab