Original ResearchBasic and Translational—Alimentary TractAltered Endoplasmic Reticulum Stress Affects Translation in Inactive Colon Tissue From Patients With Ulcerative Colitis
Section snippets
Patients and Biopsy Specimens
All patients were followed in the Department of Gastroenterology (Beaujon's hospital). The protocol was approved by the local Ethics Committee (CPP-Ile de France IV No. 2009/17), and written informed consent was obtained from all patients before enrollment. Colonic pinch biopsy specimens were obtained during endoscopic investigations in 11 patients with UC. Surgical colon samples were collected from 15 patients with UC who underwent a colectomy (Supplementary Table 1). The diagnosis of UC was
Unaffected Colonic UC Mucosa Exhibit Extended IRE1β and ATF6α Branch Signaling
UPR activation was assessed by determining IRE1β-mediated splicing of XPB-1 in unaffected colonic mucosa from UC and healthy individuals. Spliced XBP-1 (XBP-1s) mRNA levels were significantly increased in UC mucosa and the ratio of spliced to unspliced XBP-1 (XBP-1s/XBP-1u) was 1.8 and 3.8 in controls and UC, respectively (Figure 1A). Consistent with hyperactivation of the IRE1β/XBP-1 arm, increased expression of the UPR-related target genes glucose-regulated proteins (GRP94, GRP78), and ER
Discussion
There are 3 original findings in this study. First, the coordinated expression of all 3 branches of the UPR identified in controls is impaired in unaffected UC mucosa; second, unaffected UC mucosa are prone to ER stress because of impairment of the ISR; and, third, the coordinated changes in eIF2α phosphorylation, SG formation, and translation initiation selectivity identified in unaffected UC mucosa represent new approaches to understand the pathogenesis of UC.
This study shows that the 3 known
Acknowledgments
The authors thank Drs Laurence Bougnères–Vermont and Matthieu Collin from INSERM-Transfert, Dr Renato Monteiro from INSERM U699 for helpful discussions, and Sylvie Mosnier (Beaujon Hospital) for helpful technical assistance.
Electron microscopy was performed by A. Grodet in the setting of the Atelier de Microscopie ElecTronique (AMET) IFR02/CRB3. Confocal microscopy was carried out by Samira Benadda (IFR02).
References (36)
- et al.
XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease
Cell
(2008) - et al.
Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection
Gastroenterology
(2006) - et al.
Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2−/− mice
Dev Biol
(2010) - et al.
XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor
Cell
(2001) - et al.
Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation
Gastroenterology
(2007) - et al.
Stress granules: the Tao of RNA triage
Trends Biochem Sci
(2008) - et al.
Eukaryotic initiation factor 2α-independent pathway of stress granule induction by the natural product pateamine A
J Biol Chem
(2006) - et al.
Cyclin D1 and p21 in ulcerative colitis-related inflammation and epithelial neoplasia: a study of aberrant expression and underlying mechanisms
Hum Pathol
(2003) - et al.
Endoplasmic reticulum stress induced by aqueous extracts of cigarette smoke in 3T3 cells activates the unfolded-protein-response-dependent PERK pathway of cell survival
Free Radic Biol Med
(2008) - et al.
Intestinal epithelial cell signalling and chronic inflammation: from the proteome to specific molecular mechanisms
Mutat Res
(2007)
Genome-wide association study of ulcerative colitis identifies 3 new susceptibility loci, including the HNF4A region
Nat Genet
Common variants at 5 new loci associated with early-onset inflammatory bowel disease
Nat Genet
Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis
PLoS Med
Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response
Proc Natl Acad Sci U S A
Signal integration in the endoplasmic reticulum unfolded protein response
Nat Rev Mol Cell Biol
Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells
Proc Natl Acad Sci U S A
Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease
PLoS One
NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon
Mol Cell Biol
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Xavier Tréton and Eric Pédruzzi contributed equally to this work.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Association François Aupetit (AFA) (to E.O.D.), Assistance Publique-Hôpitaux de Paris (AP-HP) (to E.O.D.: Interface Fellowship), University Denis Diderot Paris 7, Société Nationale Française de Gastro-Entérologie (SNFGE), Association Française pour l'étude du foie (AFEF), Programme National de Recherche en Hépato-Gastroentérologie (PNRHGE) (to X.T. and E.O.D.), and a doctoral position from INSERM (poste d'accueil) (to X.T.).