Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of er stress and autoimmunity

Edward A. Phelps, Chiara Cianciaruso, Iacovos P. Michael, Miriella Pasquier, Jamil Kanaani, Rita Nano, Vanessa Lavallard, Nils Billestrup, Jeffrey A. Hubbell, Steinunn Baekkeskov

Research output: Contribution to journalArticle

Abstract

Pancreatic islet β-cells are particularly susceptible to endoplasmic reticulum (ER) stress, which is implicated in β-cell dysfunction and loss during the pathogenesis of type 1 diabetes (T1D). The peripheral membrane protein GAD65 is an autoantigen in human T1D. GAD65 synthesizes g-aminobutyric acid, an important autocrine and paracrine signaling molecule and a survival factor in islets. We show that ER stress in primary β-cells perturbs the palmitoylation cycle controlling GAD65 endomembrane distribution, resulting in aberrant accumulation of the palmitoylated form in trans-Golgi membranes. The palmitoylated form has heightened immunogenicity, exhibiting increased uptake by antigen-presenting cells and T-cell stimulation compared with the nonpalmitoylated form. Similar accumulation of GAD65 in Golgi membranes is observed in human β-cells in pancreatic sections from GAD65 autoantibody-positive individuals who have not yet progressed to clinical onset of T1D and from patients with T1D with residual β-cellmass and ongoing T-cell infiltration of islets. We propose that aberrant accumulation of immunogenic GAD65 in Golgi membranes facilitates inappropriate presentation to the immune system after release from stressed and/or damaged β-cells, triggering autoimmunity.

Original languageEnglish
Pages (from-to)2686-2699
Number of pages14
JournalDiabetes
Volume65
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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    Phelps, E. A., Cianciaruso, C., Michael, I. P., Pasquier, M., Kanaani, J., Nano, R., Lavallard, V., Billestrup, N., Hubbell, J. A., & Baekkeskov, S. (2016). Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of er stress and autoimmunity. Diabetes, 65(9), 2686-2699. https://doi.org/10.2337/db16-0180