000221268 001__ 221268
000221268 005__ 20180913063846.0
000221268 0247_ $$2doi$$a10.2337/db16-0180
000221268 022__ $$a1939-327X
000221268 02470 $$2ISI$$a000382099800023
000221268 037__ $$aARTICLE
000221268 245__ $$aAberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity
000221268 269__ $$a2016
000221268 260__ $$aAlexandria$$bAmer Diabetes Assoc$$c2016
000221268 300__ $$a14
000221268 336__ $$aJournal Articles
000221268 520__ $$aPancreatic 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.
000221268 700__ $$aPhelps, Edward A
000221268 700__ $$0248376$$aCianciaruso, Chiara$$g231914
000221268 700__ $$aMichael, Iacovos P
000221268 700__ $$aPasquier, Miriella
000221268 700__ $$aKanaani, Jamil
000221268 700__ $$aNano, Rita
000221268 700__ $$aLavallard, Vanessa
000221268 700__ $$aBillestrup, Nils
000221268 700__ $$0240350$$aHubbell, Jeffrey A$$g141360
000221268 700__ $$0249624$$aBaekkeskov, Steinunn$$g201728
000221268 773__ $$j65$$k9$$q2686-99$$tDiabetes
000221268 909C0 $$0252549$$pGR-STBA$$xU12906
000221268 909C0 $$0252196$$pLMRP$$xU11032
000221268 909CO $$ooai:infoscience.tind.io:221268$$pSV$$particle
000221268 917Z8 $$x182396
000221268 937__ $$aEPFL-ARTICLE-221268
000221268 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000221268 980__ $$aARTICLE