ReviewEndoplasmic reticulum stress in the intestinal epithelium and inflammatory bowel disease
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].
Section snippets
XBP1, Paneth cells and intestinal inflammation
It has recently been reported that conditional deletion of Xbp1 specifically in the small and large intestinal epithelium induces spontaneous enteritis with histological features of human inflammatory bowel disease (IBD), including neutrophilic infiltration, epithelial ulcerations, and crypt abscesses [21]. Not only is this spontaneous inflammation evident in homozygotically deleted animals but also in a significant fraction of heterozygotically deleted mice. Consistent with the interdependence
XBP1 as a genetic risk factor for Crohn's disease and ulcerative colitis
XBP1 function within the epithelium thus converges on both the regulation of the intestinal microbiota and responsiveness of the mucosal immune system to components of the intestinal microbes and as such determines the ability of the epithelium to primarily orchestrate intestinal inflammation in a cell autonomous manner. Given the central role that the relationship between the commensal microbiota and host immune responsiveness to the microbiota has for the pathogenesis of human IBD [33], [35],
ER stress and goblet cells
Goblet cells are also among the most highly secretory cells within the intestinal epithelium which provide the majority of mucus glycoproteins to the lumen and a variety of soluble mediators involved in host defense such as RELMβ [48] and trefoil factors [49]. The secretion of mucins, and other soluble mediators, not surprisingly creates a significant secretory burden on this cell type. Consistent with this, conditional deletion of Xbp1 in intestinal epithelium leads to an approximately 30%
ER stress and intestinal inflammation in humans
Increased XBP1 splicing, consistent with ER stress is observed in the colon and small intestine of subjects with both Crohn's disease and ulcerative colitis [21]. Heazlewood et al. have also reported evidence for MUC2 precursor accumulation with staining present throughout the cytoplasm in IECs from ulcerative colitis patients together with ultrastructural changes in goblet cells that are suggestive of either inappropriate granule formation or premature dissolution of stored granules prior to
Interleukin-10 and the UPR
Interleukin-10 (IL-10) is an important regulatory [67] and barrier protective [68] cytokine. In the absence of IL-10 as observed in Il10−/− mice, one of the first genetic models of intestinal inflammation, colitis and small intestinal enteritis may be observed [69]. Il10−/− mice develop colitis histologically resembling human UC when held under specific pathogen free conditions, but not under germ-free conditions [69], underscoring the importance of the commensal microbiota for the perpetuation
Intestinal microbiota and ER stress pathways in the epithelium
The identification of markers indicative of increased ER stress in the tissues and epithelia of the vast majority of human subjects with IBD analyzed to date and evidence that ER stress pathways can in and of themselves initiate and/or promote inflammation [21], [50], [66], it is logical to propose that inflammation-induced ER stress is likely to be a perpetuator of intestinal inflammation. As a corollary, it might be surmised that environmental factors which promote (or enable) the UPR might
ER stress mechanisms interact with autophagy
Genome wide association studies (GWAS) have recently identified autophagy as an important mechanism that is involved in intestinal inflammation associated with CD through the identification of genetic polymorphisms within the ATG16L1[79], [80], IRGM[81], [82], [83] and, potentially, LRRK2 genes [46], [79]. Macroautophagy represents a lysosomal pathway that is involved in the turnover of cellular macromolecules and organelles which is involved in cellular homeostasis and defense with
Conclusion
The UPR is a phylogenetically conserved mechanism involving three proximal effectors (IRE1, PERK and ATF6) that allows cells to cope with the ER stress associated with the burden of secreting high levels of protein. Through an examination of XBP1 function within the intestinal epithelium, a highly secretory cell type, it is now clear that a proper ER stress response is necessary to prevent organ specific inflammation. Deletion of Xbp1 specifically within the intestinal epithelium results in
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2021, International ImmunopharmacologyCitation Excerpt :Our findings indicated that limonin ameliorated chronic colitis by inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. More and more reports have shown that ER stress is implicated in the progression of IBD [60–62]. Highly secretory cells for instance Paneth cells and goblet cells in the intestines are especially impressionable to ER stress and largely rely on a properly functioning UPR to maintain cellular viability and homeostasis [60].