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Novel insights into the global proteome responses of insulin-producing INS-1E cells to different degrees of endoplasmic reticulum stress.

par D'Hertog, Wannes;Maris, Michael;Ferreira, Gabriela Bonfim;Verdrengh, E;Lage, Kasper;Hansen, Daniel Aaen;Cardozo, Alessandra K ;Workman, Christopher;Moreau, Yves;Eizirik, Decio L. ;Waelkens, Etienne;Overbergh, Lutgart;Mathieu, Chantal
Référence Journal of proteome research, 9, 10, page (5142-5152)
Publication Publié, 2010

Article révisé par les pairs

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Résumé :

Exposure of insulin-secreting β-cells to inflammatory cytokines or high concentrations of free fatty acids, factors involved in the pathogenesis of type 1 and type 2 diabetes, leads to endoplasmic reticulum (ER) stress, β-cell dysfunction, and eventually apoptotic β-cell death. The aim of this study was to investigate the impact of ER stress on β-cells at the protein level to evaluate the contribution of post-transcriptional and post-translational changes in ER stress-induced β-cell damage. INS-1E cells were exposed in vitro to the ER-stress inducer cyclopiazonic acid (CPA) at two concentrations, and protein changes were evaluated using 2D-DIGE. CPA, 25 μM, led to massive apoptosis, accompanied by a near complete protein translation shut-down. CPA, 6.25 μM, led to adaptation of the β-cells to ER stress. Identification of the differentially expressed proteins in the two conditions led to the discovery of a clear pattern of defense pathways, with post-translational modifications playing a crucial role. Key alterations included inhibition of insulin translation and post-translational modifications in ER chaperones HYOU1 and HSPA5. Also, a central role for 14-3-3 proteins is suggested. In conclusion, INS-1E cells are highly sensitive to ER stress, leading to important post-transcriptional and post-translational modifications that may contribute to β-cell dysfunction and death.