DFG 458716767 - TG2-Gluten

Celiac disease is a chronic, immune-mediated disorder of the small intestine triggered by the consumption of gluten proteins from wheat, rye, and barley in genetically predisposed individuals. With a global prevalence of approximately 1%, celiac disease is one of the most common food-related disorders. Due to their glutamine- and proline-rich amino acid sequences, gluten proteins are inadequately broken down by human digestive enzymes, leaving gluten peptides with nine amino acid residues and more intact, which trigger the celiac disease-specific immune cascade in the intestinal lymphoid tissue. The body's own transglutaminase 2 (TG2) plays a key role in the acquired immune response because it serves as an antigen for the formation of autoantibodies against TG2. The TG2-catalysed formation of complexes, in which TG2 multimers and TG2-gluten peptide complexes are formed, is considered crucial for the activation of T and B cells. However, the substrate specificity of TG2 and the regulation of TG2 activity in relation to the formation of TG2-gluten peptide crosslinks is largely unknown. The aim of this research project is therefore to identify the factors that regulate TG2 activity in relation to deamidation and crosslinking in order to elucidate the molecular structures of TG2-gluten peptide complexes. To this end, existing non-targeted nLC-MS/MS measurements from model experiments with TG2 and all gluten protein types from wheat, rye, and barley will first be used to identify further TG2-gluten isopeptides. Additional nLC-MS/MS measurements will be performed to verify these experimentally. Using synthetic peptide libraries, the substrate specificity of TG2 with regard to the formation of TG2-gluten peptide crosslinks will be finely mapped. By systematically varying the reaction conditions, it will be possible to deduce which factors regulate TG2 activity towards preferential deamidation or crosslink formation. The insights gained into the molecular structures of TG2-gluten peptide complexes will contribute to refining existing models of T and B cell interaction in the triggering of the celiac disease-specific autoimmune response. A deeper fundamental understanding of the mechanisms of TG2 complex formation should also contribute to a better understanding of similar processes in other autoimmune or TG-dependent diseases.

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