Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction

• Published in: Clinical and experimental immunology 2007-10, Vol.150 (1), p.49-60
• Main Authors: Harashima, S.-I, Harashima, C, Nishimura, T, Hu, Y, Notkins, A.L
• Format: Article
• Language: English
• Subjects: Akt; Analytical, structural and metabolic biochemistry; Animals; apoptosis; Apoptosis - immunology; Autoantibodies - genetics; Autoantibodies - immunology; Autoantigens - immunology; Autoantigens - metabolism; Autoimmunity; Biological and medical sciences; Carrier Proteins - metabolism; Cell Division - immunology; DNA Fragmentation; Fundamental and applied biological sciences. Psychology; G2 Phase - immunology; IA-2; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - pathology; Mice; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering - genetics; Signal Transduction - immunology; sorting nexin 19; Sorting Nexins; Transfection; Translational Studies; Tumor Cells, Cultured; Vesicular Transport Proteins - metabolism
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2007.03455.x

IA-2 is a major autoantigen in type 1 diabetes and autoantibodies to it have become important diagnostic and predictive markers. IA-2 also is an intrinsic transmembrane component of dense core secretory vesicles and knock-out studies showed that IA-2 is a regulator of insulin secretion. Here we show that overexpression of IA-2 puts mouse insulinoma MIN-6 beta cells into a pre-apoptotic state and that exposure to high glucose results in G2/M arrest and apoptosis. Molecular study revealed a decrease in phosphoinositide-dependent kinase (PDK)-1 and Akt/protein kinase B (PKB) phosphorylation. Treatment of IA-2-transfected cells with IA-2 siRNA prevented both G2/M arrest and apoptosis and increased Akt/PKB phosphorylation. A search for IA-2 interacting proteins revealed that IA-2 interacts with sorting nexin (SNX)19 and that SNX19, but not IA-2, inhibits the conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 and thereby suppresses the phosphorylation of proteins in the Akt signalling pathway resulting in apoptosis. We conclude that IA-2 acts through SNX19 to initiate the pre-apoptotic state. Our findings point to the possibility that in autoimmune diseases, tissue destruction may be autoantigen-induced, but not necessarily immunologically mediated.