Protein kinase C delta is a substrate of tissue transglutaminase and a novel autoantigen in coeliac disease

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2013-04, Vol.147 (1), p.1-8
• Main Authors: Byrne, Greg, Freeley, Michael, Feighery, Con, Whelan, Alex, Long, Aideen
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Allergy and Immunology; Autoantibodies; Autoantibodies - blood; Autoantibodies - immunology; Autoantigens - blood; Autoantigens - immunology; Autoantigens - metabolism; Blotting, Western; Celiac Disease - immunology; Celiac Disease - metabolism; Child; Coeliac disease; Enzyme-Linked Immunosorbent Assay; Female; Glutamine - genetics; Glutamine - immunology; Glutamine - metabolism; GTP-Binding Proteins - immunology; GTP-Binding Proteins - metabolism; Humans; Male; Middle Aged; Peptides - chemistry; Peptides - immunology; Peptides - metabolism; Protein Binding; Protein kinase C delta; Protein Kinase C-delta - genetics; Protein Kinase C-delta - immunology; Protein Kinase C-delta - metabolism; Protein Processing, Post-Translational - immunology; Recombinant Proteins - chemistry; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substrate Specificity; Tissue transglutaminase; Transglutaminases - immunology; Transglutaminases - metabolism; Young Adult
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2013.01.007

Abstract Post-translational modification of proteins by deamidation or transamidation by tissue transglutaminase (tTG) has been suggested as a possible mechanism for the development of autoimmunity. Sequence analysis of protein kinase C delta (PKCδ) identified an amino acid motif that suggested the possibility that PKCδ was a glutamine substrate of tTG and MALDI-TOF analysis of synthesised peptides from PKCδ proved that this was the case. Polymerisation experiments using recombinant tTG and biotinylated hexapeptide substrate incorporation assays demonstrated that PKCδ is a substrate for tTG-mediated transamidation. Elevated levels of anti-PKCδ antibodies were detected in sera from patients with coeliac disease (p < 0.0001) but not from patients with other autoimmune disorders. These data suggest that a subset of patients with coeliac disease produce autoantibodies against PKCδ and that this response may stem from a tTG–PKCδ substrate interaction.