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- Title
Gliadin Peptides Induce Tissue Transglutaminase Activation and ER-Stress through Ca<sup>2+</sup> Mobilization in Caco-2 Cells.
- Authors
Caputo, Ivana; Secondo, Agnese; Lepretti, Marilena; Paolella, Gaetana; Auricchio, Salvatore; Barone, Maria Vittoria; Esposito, Carla; Gasset, Maria
- Abstract
Background: Celiac disease (CD) is an intestinal inflammatory condition that develops in genetically susceptible individuals after exposure to dietary wheat gliadin. The role of post-translational modifications of gliadin catalyzed by tissue transglutaminase (tTG) seems to play a crucial role in CD. However, it remains to be established how and where tTG is activated in vivo. We have investigated whether gliadin peptides modulate intracellular Ca2+ homeostasis and tTG activity. Methods/Principal Findings: We studied Ca2+ homeostasis in Caco-2 cells by single cell microfluorimetry. Under our conditions, A-gliadin peptides 31-43 and 57-68 rapidly mobilized Ca2+ from intracellular stores. Specifically, peptide 31-43 mobilized Ca2+ from the endoplasmic reticulum (ER) and mitochondria, whereas peptide 57-68 mobilized Ca2+ only from mitochondria. We also found that gliadin peptide-induced Ca2+ mobilization activates the enzymatic function of intracellular tTG as revealed by in situ tTG activity using the tTG substrate pentylamine-biotin. Moreover, we demonstrate that peptide 31-43, but not peptide 57-68, induces an increase of tTG expression. Finally, we monitored the expression of glucose- regulated protein-78 and of CCAAT/enhancer binding protein-homologous protein, which are two biochemical markers of ER-stress, by real-time RT-PCR and western blot. We found that chronic administration of peptide 31-43, but not of peptide 57-68, induces the expression of both genes. Conclusions: By inducing Ca2+ mobilization from the ER, peptide 31-43 could promote an ER-stress pathway that may be relevant in CD pathogenesis. Furthermore, peptides 31-43 and 57-68, by activating intracellular tTG, could alter inflammatory key regulators, and induce deamidation of immunogenic peptides and gliadin-tTG crosslinking in enterocytes and specialized antigen-presenting cells.
- Subjects
CELIAC disease; GLIADINS; POST-translational modification; LIVER diseases; CROSSLINKING (Polymerization); POLYMERASE chain reaction
- Publication
PLoS ONE, 2012, Vol 7, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0045209