Aberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity

作者：Phelps Edward A; Cianciaruso Chiara; Michael Iacovos P; Pasquier Miriella; Kanaani Jamil; Nano Rita; Lavallard Vanessa; Billestrup Nils; Hubbell Jeffrey A; Baekkeskov Steinunn^*

来源：Diabetes, 2016, 65(9): 2686-2699.

DOI：10.2337/db16-0180

Pancreatic islet beta-cells are particularly susceptible to endoplasmic reticulum (ER) stress, which is implicated in beta-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 gamma-aminobutyric acid, an important autocrine and paracrine signaling molecule and a survival factor in islets. We show that ER stress in primary beta-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 beta-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 beta-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 beta-cells, triggering autoimmunity.

• 出版日期2016-9