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

17 Citations (Scopus)

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

Fingerprint

Autoantigens
Autoimmunity
Type 1 Diabetes Mellitus
Endoplasmic Reticulum Stress
Membranes
Islets of Langerhans
Autocrine Communication
Paracrine Communication
Lipoylation
Aminobutyrates
T-Lymphocytes
Antigen-Presenting Cells
Autoantibodies
Immune System
Membrane Proteins
Survival

ASJC Scopus subject areas

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

Cite this

Phelps, E. A., Cianciaruso, C., Michael, I. P., Pasquier, M., Kanaani, J., Nano, R., ... 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

Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of er stress and autoimmunity. / Phelps, Edward A.; Cianciaruso, Chiara; Michael, Iacovos P.; Pasquier, Miriella; Kanaani, Jamil; Nano, Rita; Lavallard, Vanessa; Billestrup, Nils; Hubbell, Jeffrey A.; Baekkeskov, Steinunn.

In: Diabetes, Vol. 65, No. 9, 01.09.2016, p. 2686-2699.

Research output: Contribution to journalArticle

Phelps, EA, Cianciaruso, C, Michael, IP, Pasquier, M, Kanaani, J, Nano, R, Lavallard, V, Billestrup, N, Hubbell, JA & Baekkeskov, S 2016, 'Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of er stress and autoimmunity', Diabetes, vol. 65, no. 9, pp. 2686-2699. https://doi.org/10.2337/db16-0180
Phelps, Edward A. ; Cianciaruso, Chiara ; Michael, Iacovos P. ; Pasquier, Miriella ; Kanaani, Jamil ; Nano, Rita ; Lavallard, Vanessa ; Billestrup, Nils ; Hubbell, Jeffrey A. ; Baekkeskov, Steinunn. / Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of er stress and autoimmunity. In: Diabetes. 2016 ; Vol. 65, No. 9. pp. 2686-2699.
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