Endoplasmic reticulum stress in the intestinal epithelium and inflammatory bowel disease

Abstract

The unfolded protein response as a consequence of endoplasmic reticulum (ER) stress has recently been implicated as a novel mechanism that may lead to inflammatory bowel disease (IBD). Impairment of proper ER stress resolution in highly secretory Paneth and, to a lesser extent, goblet cells within the epithelium can primarily lead to intestinal inflammation. An inability to manage ER stress may not only be a primary originator of intestinal inflammation as exemplified by genetic polymorphisms in XBP1 that are associated with IBD but also a perpetuator of inflammation when ER stress is induced secondarily to inflammatory mediators or microbial factors. Furthermore, ER stress pathways may interact with other processes that lead to IBD, notably autophagy.

Introduction

The endoplasmic reticulum (ER) stress response allows cells to deal with endogenous stress induced by misfolded proteins via a mechanism that is termed the unfolded protein response (UPR) [1], [2]. Three proximal effectors of the unfolded protein response exist in mammalian cells that sense the accumulation of misfolded proteins. These include inositol-requiring transmembrane kinase/endonuclease 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6 (ATF6). Under homeostatic conditions, in the absence of significant protein misfolding, IRE1, PERK and ATF6 exist in an inactive state through an association with immunoglobulin-heavy-chain-binding protein (BIP) which is also known as glucose regulated protein 78 (GRP78). As a chaperone, BIP associates with and thus senses unfolded proteins within the lumen of the ER resulting in the conversion of IRE1, PERK and ATF6 into an active state and consequently the ability to regulate cellular events that accommodate the cell's ability to respond to the accumulation of unfolded proteins. The cellular survival pathway that is controlled by IRE1, PERK and ATF6 is primarily mediated by downstream transcription factors. In its active state, PERK is autophosphorylated and also phosphorylates and thus inhibits eukaryotic translation-initiation factor 2α (EIF2α) resulting in the cessation of translation. The mRNA encoding activating transcription factor 4 (ATF4) is however resistant to EIF2α inhibition allowing for ATF4 production and accumulation during periods of ER stress. Similarly, during ER stress and release from BIP-mediated suppression, ATF6 is mobilized to the Golgi apparatus where its cytoplasmic tail is subject to cleavage by site-1 protease (S1P) resulting in release of a fragment of the ATF6 cytoplasmic tail (ATF6f) which is also transcriptionally active. ATF6f and ATF4 bind to endoplasmic reticulum stress element (ERSE) and unfolded protein response element (UPRE) motifs, respectively, thus directing transcriptional programs which affect protein synthesis, folding and secretion, expansion of the ER, the degradation of unfolded proteins and, ultimately, programmed cell death in the most extreme circumstance. The UPR thus allows for cellular adaptation and survival to occur in response to the accumulation of misfolded proteins within the ER.

The third arm of the UPR involves IRE1; the focus of this review. IRE1 is the most conserved among the three limbs of the UPR [3], [4]. IRE1 consists of two structurally related proteins that are present in eukaryotic cells. These include the ubiquitously expressed IRE1α and IRE1β whose expression is restricted to the intestinal epithelium [5]. IRE1 is an ER resident 110 kD transmembrane protein that upon activation trans-autophosphorylates, similar to PERK, and functions as an endoribonuclease and protein kinase. The endoribonuclease function of IRE1 removes a 26 bp nucleotide stretch from cytosolic unspliced XBP1 (XBP1u) mRNA to generate a spliced version of XBP1 (XBP1s). Splicing of XBP1 leads to a frame-shift that when translated results in a modification of the carboxy-terminal portion of XBP1. Relative to XBP1u, which is highly unstable and transcriptionally inert, XBP1s functions as a potent transcription factor that binds to UPRE motifs associated with its transcriptional program [6], [7], [8], [9], [10]. XBP1s transactivates a core set of UPR target genes in all cell types, and a remarkably diverse set of genes in a condition- and cell type-specific manner that contribute to cellular adaptation in response to ER stress [11], [12], [13]. XBP1 is itself a transcriptional target of ATF6f showing the significant cross-talk that exists between the three arms of the UPR [2].

XBP1 is extremely important for the function (and survival) of highly secretory cells which are especially vulnerable to ER stress given their need to process and secrete high quantities of protein through the secretory pathway. These cell types include plasma cells [14], [15], hepatocytes [16], pancreatic acinar cells [17] and plasmacytoid dendritic cells [18] whose homeostatic regulation requires normal XBP1 function. Moreover, it can be envisioned that these cell types are especially susceptible to environmental factors that further drive ER stress through disrupting protein quality control measures associated with the ER as would occur during hypoxia, calcium deprivation, disruption of proteasome function and other metabolic irregularities and hyperproliferative states [2]. As such, ER stress has been increasingly recognized to be both a secondary consequence of neoplasia and inflammation [2], [19], [20] as well as a primary factor that is involved in inducing inflammation and potentially cancer in special tissue environments [21].