气候变化领域集成服务门户(CCPortal): Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation

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DOI	10.1073/pnas.2023871118
	Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation
	Cartwright I.M.; Dowdell A.S.; Lanis J.M.; Brink K.R.; Mu A.; Kostelecky R.E.; Schaefer R.E.M.; Welch N.; Onyiah J.C.; Hall C.H.T.; Gerich M.E.; Tabor J.J.; Colgan S.P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:20
英文摘要	Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enriched in cyclic AMP response element-binding protein (CREB)-regulated gene targets. Utilizing loss- and gain-of-function approaches in cultured epithelia and murine colonoids, we demonstrate that EA elicits prominent CREB phosphorylation through cyclic AMPindependent mechanisms that requires elements of the mitogenactivated protein kinase signaling pathway. Further analysis revealed that EA signals through the G protein-coupled receptor GPR31 to promote induction of FosB, NR4A1, and DUSP1. These studies were extended to an in vivo murine model in conjunction with colonization of a pH reporter Escherichia coli strain that demonstrated significant mucosal acidification in the TNFAΔARE model of murine ileitis. Herein, we observed a strong correlation between the expression of acidosis-associated genes with bacterial reporter sfGFP intensity in the distal ileum. Finally, the expression of this unique EA-associated gene signature was increased during active inflammation in patients with Crohn's disease but not in the patient control samples. These findings establish a mechanism for EA-induced signals during inflammation-associated acidosis in both murine and human ileitis. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Acidosis; CREB phosphorylation; GPR31; Intestinal epithelial cells; Mitogen-activated protein kinase
语种	英语
scopus关键词	cyclic AMP; cyclic AMP responsive element binding protein; G protein coupled receptor; green fluorescent protein; mitogen activated protein kinase; mitogen activated protein kinase phosphatase 1; nuclear receptor Nur77; RNA; transcription factor FosB; antiporter; Creb1 protein, mouse; cyclic AMP responsive element binding protein; Dusp1 protein, mouse; Fosb protein, mouse; G protein coupled receptor; Gpr31 protein, mouse; mitogen activated protein kinase; mitogen activated protein kinase phosphatase 1; Nr4a1 protein, mouse; nuclear receptor Nur77; protein c fos; Slc26a3 protein, mouse; acidification; acidosis; animal tissue; Article; bacterial colonization; cell culture; colonoid; controlled study; correlation analysis; Crohn disease; disease association; epithelium cell; Escherichia coli; gain of function mutation; gene expression; gene targeting; human; human cell; human tissue; ileitis; in vivo study; inflammation; intestine epithelium cell; loss of function mutation; MAPK signaling; molecular mechanics; mouse; mouse model; mucosal acidosis; nonhuman; pH; priority journal; protein induction; protein phosphorylation; RNA sequencing; acidosis; animal; C57BL mouse; disease model; gene expression regulation; genetics; ileum; intestine mucosa; metabolism; organoid; pathology; phosphorylation; sequence analysis; signal transduction; Acidosis; Animals; Antiporters; Crohn Disease; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Dual Specificity Phosphatase 1; Gene Expression Regulation; Humans; Ileitis; Ileum; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Nuclear Receptor Subfamily 4, Group A, Member 1; Organoids; Phosphorylation; Proto-Oncogene Proteins c-fos; Receptors, G-Protein-Coupled; Sequence Analysis, RNA; Signal Transduction; Sulfate Transporters
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251185
作者单位	Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Pathology, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO 80045, United States; Systems, Synthetic, and Physical Biology Ph.D. Program, Rice University, Houston, TX 77005, United States; Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, Aurora, CO 80045, United States; Department of Bioengineering, Rice University, Houston, TX 77005, United States; Department of Biosciences, Rice University, Houston, TX 77005, United States
推荐引用方式 GB/T 7714	Cartwright I.M.,Dowdell A.S.,Lanis J.M.,et al. Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation[J],2021,118(20).
APA	Cartwright I.M..,Dowdell A.S..,Lanis J.M..,Brink K.R..,Mu A..,...&Colgan S.P..(2021).Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.Proceedings of the National Academy of Sciences of the United States of America,118(20).
MLA	Cartwright I.M.,et al."Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation".Proceedings of the National Academy of Sciences of the United States of America 118.20(2021).