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  4. Aberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity
 
research article

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
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2016
Diabetes

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 γ-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-cell mass 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.

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Type
research article
DOI
10.2337/db16-0180
Web of Science ID

WOS:000382099800023

Author(s)
Phelps, Edward A
Cianciaruso, Chiara  
Michael, Iacovos P
Pasquier, Miriella
Kanaani, Jamil
Nano, Rita
Lavallard, Vanessa
Billestrup, Nils
Hubbell, Jeffrey A  
Baekkeskov, Steinunn  
Date Issued

2016

Publisher

Amer Diabetes Assoc

Published in
Diabetes
Volume

65

Issue

9

Start page

2686

End page

99

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
GR-STBA  
LMRP  
Available on Infoscience
September 12, 2016
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/129264
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