A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux.
Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes.
['Krokowski|Dawid|D|', 'Han|Jaeseok|J|', 'Saikia|Mridusmita|M|', 'Majumder|Mithu|M|', 'Yuan|Celvie L|CL|', 'Guan|Bo-Jhih|BJ|', 'Bevilacqua|Elena|E|', 'Bussolati|Ovidio|O|', 'Bröer|Stefan|S|', 'Arvan|Peter|P|', 'Tchórzewski|Marek|M|', 'Snider|Martin D|MD|', 'Puchowicz|Michelle|M|', 'Croniger|Colleen M|CM|', 'Kimball|Scot R|SR|', 'Pan|Tao|T|', 'Koromilas|Antonis E|AE|', 'Kaufman|Randal J|RJ|', 'Hatzoglou|Maria|M|']
D051701:Activating Transcription Factor 4 D026905:Amino Acid Transport Systems D000596:Amino Acids D000604:Amino Acyl-tRNA Synthetases D000818:Animals D017209:Apoptosis D002470:Cell Survival D003924:Diabetes Mellitus, Type 2 D059865:Endoplasmic Reticulum Stress D015852:Eukaryotic Initiation Factor-2 D057809:HEK293 Cells D006801:Humans D050417:Insulin-Secreting Cells D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D010766:Phosphorylation D014176:Protein Biosynthesis D011499:Protein Processing, Post-Translational D012343:RNA, Transfer D015533:Transcriptional Activation
Diabetes ER Stress Amino Acid Transport Aminoacyl tRNA Synthetase Beta Cell Glutamine