Epithelial ER Stress in Crohn's Disease and Ulcerative Colitis

BASIC SCIENCE REVIEW ARTICLE Epithelial ER Stress in Crohn’s Disease and Ulcerative Colitis Stewart S. Cao, PhD Abstract: Research in the past decade has greatly expanded our understanding of the pathogenesis of inflammatory bowel disease, which includes (Inflamm Bowel Dis 2016;22:984–993) Key Words: unfolded protein response, intestinal epithelial cells, inflammatory bowel disease I nflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) is one of the most common inflammatory diseases in the United States and Europe.1 The incidence of IBD is rising in regions such as Eastern Asia where it used to be an uncommon condition.2 First described dozens of years ago, the etiology of CD and UC remains incompletely understood. Recent 2 decades witnessed the dramatic progress in our understanding of the pathoimmunology of IBD. This knowledge has been translated into treatments, which include mesalazine, immunosuppressants, steroids, and the burgeoning biologics. However, a subset of patients fails to respond to any of these immune-targeting therapies. For those who initially respond well, it is often challenging to maintain long-term remission. In addition to the suppression of mucosal inflammation, recent studies indicated that the healing of the mucosa itself, including restoration of the epithelial layer, is associated with long-term remission and lower risk of exacerbations that require surgery.3 The importance of the intestinal epithelium in mucosal homeostasis has also been demonstrated by numerous animal studies and genome-wide association studies that identified genes closely related to epithelial functions. Cellular stress signaling Received for publication October 7, 2015; Accepted October 7, 2015. From the Columbia University College of Physicians and Surgeons, New York, New York. The author has no conflicts of interest to disclose. Reprints: Stewart S. Cao, PhD, Columbia University College of Physicians and Surgeons, 652 W. 163rd street, #64, New York, NY 10032 (e-mail: sc3676@cumc. columbia.edu). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000660 Published online 7 March 2016. 984 | www.ibdjournal.org including endoplasmic reticulum (ER) stress, oxidative stress, autophagy, and mitochondrial homeostasis has been linked to the differentiation, maintenance, and normal function of multiple epithelial cell populations in the gut.4 Patients with IBD exhibit signs of ER stress in their ileal and/or colonic epithelia with active disease.5–7 Further understanding of ER stress and the unfolded protein response (UPR) in intestinal epithelial cells (IECs) may help fill the gap in current IBD therapy. THREE BRANCHES OF THE UPR IRE1-XBP1 Pathway Inositol-requiring enzyme 1 (IRE1) is the most conserved ER stress sensor and a type I transmembrane protein with an endoribonuclease domain and a serine/threonine kinase domain in its cytosolic portion. IRE1a is expressed ubiquitously in mammalian tissues, whereas IRE1b expression is primarily detected in the epithelial cells in the digestive and respiratory tracts. On ER stress, activated IRE1a cleaves a 26-base intron at the dual stem loop structure of an mRNA that is then translated to produce the X-box–binding protein 1 (XBP1), a cAMP response element–binding (CREB) protein/activating transcription factor (ATF) basic leucine zipper (bZIP)-containing transcription factor.8 The tRNA ligase RTCB and its cofactor archease were recently identified to catalyze unconventional XBP1 mRNA splicing in human cells on ER stress.9 XBP1s induce genes that control a variety of ER-related functions: protein folding, maturation, transport, phospholipid biosynthesis, ER expansion, and ER-associated protein degradation (ERAD). In addition to cleaving Xbp1 mRNA, the endoribonuclease domain of IRE1a targets a subset of ER-localized mRNAs for Inflamm Bowel Dis  Volume 22, Number 4, April 2016 Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited. Crohn’s disease and ulcerative colitis. In addition to the sophisticated network of immune response, the epithelial layer lining the mucosa has emerged as an essential player in the development and persistence of intestinal inflammation. As the frontline of numerous environmental insults in the gut, the intestinal epithelial cells are subject to various cellular stresses. In eukaryotic cells, disturbance of endoplasmic reticulum homeostasis may lead to the accumulation of unfolded and misfolded proteins in the ER lumen, a condition called ER stress. This cellular process activates the unfolded protein response, which functions to enhance the ER protein folding capacity, alleviates the burden of protein synthesis and maturation, and activates ER-associated protein degradation. Paneth and goblet cells, 2 secretory epithelial populations in the gut, are particularly sensitive to ER stress on environmental or genetic disturbances. Recent studies suggested that epithelial ER stress may contribute to the pathogenesis of Crohn’s disease and ulcerative colitis by compromising protein secretion, inducing epithelial cell apoptosis and activating proinflammatory response in the gut. Our knowledge of ER stress in intestinal epithelial function may open avenue to new inflammatory bowel disease therapies by targeting the ER protein folding homeostasis in the cells lining the intestinal mucosa. Inflamm Bowel Dis  Volume 22, Number 4, April 2016 PERK-eIF2a Pathway Pancreatic ER eIF2a kinase (PERK) is a type I transmembrane protein with a serine/threonine kinase domain on the cytosolic side. A recent study of the crystal structure of human PERK luminal domain revealed a new tetramer arrangement, which is required for the phosphorylation of PERK on ER stress.18 Activated PERK phosphorylates the a subunit of eukaryotic translation initiation factor 2 (eIF2a) on Ser51, which then suppresses global translation initiation of mRNAs, thereby mitigating the ER protein folding load. In addition, PERK was shown to impact cell fate decision through the activation of cellular inhibitor of apoptosis and nuclear respiratory factor 2 in ER-stressed cells.19 In mammals, there are 3 cytosolic kinases: dsRNA-activated protein kinase (PKR), hemeregulated eIF2a kinase, and general control nonrepressed 2 kinase that phosphorylate Ser51 in eIF2a. Those kinases respond to a broad spectrum of cellular stresses through eIF2a phosphorylation and its downstream signaling, which was named the integrated stress response. In most mammalian cells, eIF2a phosphorylation can be normally reversed by protein phosphatase 1 regulatory subunits GADD34 and CReP. Although most protein synthesis is inhibited by eIF2a phosphorylation, a subset of mRNAs, including an mRNA encoding bZIP transcription factor ATF4, is selectively translated by phosphorylated eIF2a. ATF4 regulates multiple aspects of the UPR, which include ER ch (...truncated)