Ca2+ Mobilization Induced by Gliadin Figure 9. A model of the possible relationship between gliadin peptides, tTG activation, ER-stress and the inflammatory response. Toxic and immunogenic gliadin peptides penetrate inside the cells through vesicular trafficking (1) [14,18,20] and rapidly induce Ca2+ release from the ER (2) and mitochondria (3). The increased [Ca2+]i activates normally silent tTG (4), which in turn deamidates gliadin peptides (5) and/or produces cross-links between the peptides and the tTG itself (6) or between the peptides and other cellular proteins [4,5,11,12]. In addition, active tTG transamidates IkBa [38], PPARc [18], and Rho A [36], which are key regulators of the inflammatory response. Persistent stimulation with toxic gliadin peptides (p31–43) can also trigger an ER-stress response (8) that, in turn, can modulate the expression of inflammatory genes (9) [45]. doi:10.1371/journal.pone.0045209.g009 Acknowledgments We are grateful to Jean Ann Gilder (Scientific Communication srl) for text editing and to the ‘‘Fondazione per il Sud’’. References 1. Jabri B, Sollid LM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 9(12): 858–870. 2. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, et al. (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362(9377): 30–37. 3. Tollefsen S, Arentz-Hansen H, Fleckenstein B, Fleckenstein B, Molberg O, et al. (2006) HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 116(8): 2226–2236. 4. Sollid LM (2000) Molecular basis of celiac disease. Annu Rev Immunol 18: 53– 81. 5. Sollid LM, Jabri B (2011) Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr Opin Immunol 23(6): 732–738. 6. Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4(2): 140–156. Author Contributions Conceived and designed the experiments: IC CE SA AS MVB. Performed the experiments: IC AS ML GP. Analyzed the data: IC AS CE SA MVB. Contributed reagents/materials/analysis tools: CE AS SA. Wrote the paper: IC CE. 7. Im MJ, Russell MA, Feng JF (1997) Transglutaminase II: a new class of GTP- binding protein with new biological functions. Cell Signal 9(7): 477–482. 8. Zemskov EA, Mikhailenko I, Hsia RC, Zaritskaya L, Belkin AM (2011) Unconventional secretion of tissue transglutaminase involves phospholipid- dependent delivery into recycling endosomes. PLoS One 6(4): e19414. 9. Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368: 377–396. 10. Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 89(3): 991–1023. 11. Sollid LM, Molberg O, McAdam S, Lundin KE (1997) Autoantibodies in coeliac disease: tissue transglutaminase-guilt by association? Gut 41(6): 851–852. 12. Schuppan D, Dieterich W, Riecken EO (1998) Exposing gliadin as a tasty food for lymphocytes. Nat Med 4(6): 666–667. PLOS ONE | www.plosone.org 11 September 2012 | Volume 7 | Issue 9 | e45209