Anti-tissue transglutaminase antibodies activate intracellular tissue transglutaminase by modulating cytosolic Ca2+ homeostasis.
Anti-tissue transglutaminase (tTG) antibodies are specifically produced in the small-intestinal mucosa of celiac disease (CD) patients. It is now recognized that these antibodies, acting on cell-surface tTG, may play an active role in CD pathogenesis triggering an intracellular response via the activation of different signal transduction pathways. In this study, we report that anti-tTG antibodies, both commercial and from a CD patient, induce a rapid Ca(2+) mobilization from intracellular stores in Caco-2 cells. We characterized the mechanism of Ca(2+) release using thapsigargin and carbonylcyanide-p-trifluoromethoxyphenylhydrazone, which are able to deplete specifically endoplasmic reticulum and mitochondria of Ca(2+), respectively. Our data highlight that both pathways of calcium release were involved, thus indicating that the spectrum of cellular responses downstream can be very wide. In addition, we demonstrate that the increased Ca(2+) level in the cells evoked by anti-tTG antibodies was sufficient to activate tTG, which is normally present as a latent protein due to the presence of low Ca(2+) and to the inhibitory effect of GTP/GDP. Herein, we discuss the importance of intracellular tTG activation as central in the context of CD pathogenesis.
Department of Chemistry and Biology, University of Salerno, via Ponte Don Melillo, 84084 Fisciano (Salerno), Italy.
Ivana
I
Caputo
Marilena
M
Lepretti
Agnese
A
Secondo
Stefania
S
Martucciello
Gaetana
G
Paolella
Daniele
D
Sblattero
Maria Vittoria
MV
Barone
Carla
C
Esposito
D001323:Autoantibodies / Q000494:pharmacology*; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002446:Celiac Disease / Q000201:enzymology / Q000276:immunology; D002462:Cell Membrane / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
D001323:Autoantibodies; D004791:Enzyme Inhibitors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium