Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction.
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.
Harashima
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SI
Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, Maryland 20892, USA.
Harashima
C
C
Nishimura
T
T
Hu
Y
Y
Notkins
A L
AL
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D053938:DNA Fragmentation; D016195:G2 Phase / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D058305:Sorting Nexins; D014162:Transfection; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D002352:Carrier Proteins; C096322:ICA512 autoantibody; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; C524095:Snx19 protein, mouse; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt