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

  1. S.-I. Harashima1,
  2. C. Harashima2,
  3. T. Nishimura1,
  4. Y. Hu1,
  5. A. L. Notkins1,*

Article first published online: 28 AUG 2007

DOI: 10.1111/j.1365-2249.2007.03455.x

Issue

Clinical & Experimental Immunology

Clinical & Experimental Immunology

Volume 150, Issue 1, pages 49–60, October 2007

Additional Information

How to Cite

Harashima, S.-I., Harashima, C., Nishimura, T., Hu, Y. and Notkins, A. L. (2007), Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction. Clinical & Experimental Immunology, 150: 49–60. doi: 10.1111/j.1365-2249.2007.03455.x

Author Information

  1. 1

    Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, Maryland 20892, USA, and

  2. 2

    Department of Anatomy, Physiology and Genetics, USUHS School of Medicine, Bethesda, Maryland 20814, USA

*Abner Louis Notkins MD, Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD 20892, USA. E-mail: anotkins@mail.nih.gov

Publication History

  1. Issue published online: 28 AUG 2007
  2. Article first published online: 28 AUG 2007
  3. Accepted for publication 4 June 2007

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Keywords:

  • Akt;
  • apoptosis;
  • autoimmunity;
  • IA-2;
  • sorting nexin 19

Summary

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.

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