A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux

Dawid Krokowski, Jaeseok Han, Mridusmita Saikia, Mithu Majumder, Celvie L. Yuan, Bo Jhih Guan, Elena Bevilacqua, Ovidio Bussolati, Stefan Broër, Peter Arvan, Marek Tchoŕzewski, Martin D. Snider, Michelle Puchowicz, Colleen M. Croniger, Scot R. Kimball, Tao Pan, Antonis E. Koromilas, Randal J. Kaufman, Maria Hatzoglou

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17202-17213
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number24
DOIs
StatePublished - Jun 14 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Krokowski, D., Han, J., Saikia, M., Majumder, M., Yuan, C. L., Guan, B. J., Bevilacqua, E., Bussolati, O., Broër, S., Arvan, P., Tchoŕzewski, M., Snider, M. D., Puchowicz, M., Croniger, C. M., Kimball, S. R., Pan, T., Koromilas, A. E., Kaufman, R. J., & Hatzoglou, M. (2013). A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux. Journal of Biological Chemistry, 288(24), 17202-17213. https://doi.org/10.1074/jbc.M113.466920