Proline-Rich Acidic Protein 1 (PRAP1) Protects the Gastrointestinal Epithelium From Irradiation-Induced Apoptosis

• Type of Material: Article
• Authors: Alexandra A. Wolfarth, Emory University; Xu Liu, Emory University; Trevor M. Darby, Emory University; Darra J. Boyer, Emory University; Jocelyn B. Spizman, Emory University; Joshua A. Owens, Emory University; Bindu Chandrasekharan, Emory University; Crystal R. Naudin, Emory University; Krisztina Hanley, Emory University; Brian Robinson, Emory University; Eric Ortlund, Emory University; Rheinallt Jones, Emory University; Andrew Neish, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: ELSEVIER INC
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcmgh.2020.06.011
• Title of Journal or Parent Work: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
• Volume: 10
• Issue: 4
• Start Page: 713
• End Page: 727
• Grant/Funding Information: Supported by American Heart Association postdoctoral fellowship 17POST33660110 (X.L.); by the Crohn's and Colitis Foundation Award (T.M.D.); by American Heart Association fellowship 19POST34370006 (C.R.N.); and supported in part by National Institutes of Health grants R01DK095750 (E.A.O.), R01DK098391 and R01CA179424 (R.M.J.), and R01DK071604 and R01AI064462 (A.S.N.).
• Keywords: Life Sciences & Biomedicine; Oxidative Stress; p21; METABOLISM; INTESTINAL EPITHELIUM; Gastroenterology & Hepatology; Small Intestine; MUCOSA; PROLIFERATION; P21(WAF1/CIP1); Intrinsically Disordered Proteins; DISEASE; MICROBIOTA; STRESS; Science & Technology; UTERUS; GROWTH ARREST
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Obstetrics and Gynecology

Abstract

Background & Aims: The intestinal epithelium must be resilient to physiochemical stress to uphold the physiological barrier separating the systemic compartment from the microbial and antigenic components of the gut lumen. Identifying proteins that mediate protection and enhancing their expression is therefore a clear approach to promote intestinal health. We previously reported that oral ingestion of the probiotic Lactobacillus rhamnosus GG not only induced the expression of several recognized cytoprotective factors in the murine colon, but also many genes with no previously described function, including the gene encoding proline-rich acidic protein 1 (PRAP1). PRAP1 is a highly expressed protein in the epithelium of the gastrointestinal tract and we sought to define its function in this tissue. Methods: Purified preparations of recombinant PRAP1 were analyzed biochemically and PRAP1 antisera were used to visualize localization in tissues. Prap1-/- mice were characterized at baseline and challenged with total body irradiation, then enteroids were generated to recapitulate the irradiation challenge ex vivo. Results: PRAP1 is a 17-kilodalton intrinsically disordered protein with no recognizable sequence homology. PRAP1 expression levels were high in the epithelia of the small intestine. Although Prap1-/- mice presented only mild phenotypes at baseline, they were highly susceptible to intestinal injury upon challenge. After irradiation, the Prap1-/- mice showed accelerated death with a significant increase in apoptosis and p21 expression in the small intestinal epithelium. Conclusions: PRAP1 is an intrinsically disordered protein highly expressed by the gastrointestinal epithelium and functions at exposed surfaces to protect the barrier from oxidative insult.