Aberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity.
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.
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Edward A
EA
Phelps
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Chiara
C
Cianciaruso
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Iacovos P
IP
Michael
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Miriella
M
Pasquier
Departments of Medicine, Microbiology and Immunology and Diabetes Center, University of California San Francisco, San Francisco, CA.
Jamil
J
Kanaani
Diabetes Research Institute, IRCCS, Pancreatic Islet Processing Facility, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Rita
R
Nano
Cell Isolation and Transplantation Center, Faculty of Medicine, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Vanessa
V
Lavallard
Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nils
N
Billestrup
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Institute for Molecular Engineering, University of Chicago, Chicago, IL.
Jeffrey A
JA
Hubbell
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Departments of Medicine, Microbiology and Immunology and Diabetes Center, University of California San Francisco, San Francisco, CA steinunn.baekkeskov@epfl.ch.
Steinunn
S
Baekkeskov
D000818:Animals; D001323:Autoantibodies; D001324:Autoantigens / Q000378:metabolism*; D015551:Autoimmunity / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D054878:Lipoylation; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2