Abstract
The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which TonEBP was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy.
Highlights
The endoplasmic reticulum (ER) is an important intracellular organelle for the synthesis, folding, and assembly of secreted and transmembrane proteins
To investigate the role of Tonicity-responsive enhancer-binding protein (TonEBP) in β-cell survival under ER stress, we first examined whether the siRNA-mediated depletion of TonEBP affects cell death triggered by agents that induce ER stress, namely, brefeldin A (BFA) and tunicamycin (TM)
MIN6-M9 mouse β-cells transfected with scrambled siRNA or TonEBP-targeted siRNA were incubated with 20 μM BFA or 1 μg/mL TM for 24 h followed by an Lactate dehydrogenase (LDH) or MTT assay
Summary
The endoplasmic reticulum (ER) is an important intracellular organelle for the synthesis, folding, and assembly of secreted and transmembrane proteins. ER function is disturbed in several physiological and pathological conditions, and this leads to ER stress, which is characterized by the accumulation and aggregation of unfolded and/or misfolded proteins in the ER [1,2]. An insufficient UPR and/or persistent ER stress trigger cellular dysfunction and cell death, leading to human diseases [2,3,4]. Β-cells in pancreatic islets contain a highly developed ER to produce insulin and are vulnerable to ER stress [5]. ER stress and the UPR are being increasingly implicated in the dysfunction and loss of pancreatic β-cells associated with the development of type 1 and type 2 diabetes mellitus (DM) [6,7]
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