TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy

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.

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4‐S100A9 Pathway in Acute Lymphoblastic Leukemia

“…To confirm the contribution of NFAT5 to cell survival after PSPA treatment, MG‐132, an NFAT5 inducer, [40] was applied to reverse the apoptosis induced by PSPAs. As shown in Figure 7 A and 7B , the apoptotic rate was completely reestablished by the MG‐132 pretreatment.…”

Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

“…128 Moreover, tonicity-responsive enhancer-binding protein (To-nEBP), also known as nuclear factor of activated T-cells 5 (NFAT5), enhances β-cell survival by enhancing autophagy. 129 However, its effects on several novel agents in β-cells have not been well studied. Future studies should investigate the effects of autophagy enhancers on β-cell apoptosis and dysfunction.…”

Special Issue on “Ubiquitin and Autophagy”

“…The “Ubiquitin and Autophagy” Special Issue features 13 papers: seven research articles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ] and six reviews [ 8 , 9 , 10 , 11 , 12 , 13 ]. All of them are at the intersection of ubiquitin-related processes and autophagy, including the roles of: (1) ATG and UBL proteins in the UPS and autophagy [ 2 , 3 ], (2) ubiquitin-binding autophagic receptor, p62, in autophagy signaling [ 4 ], (3) LC3-interacting region (LIR) of connexins in binding to UBL proteins [ 6 ], (4) proteasomal deubiquitinating enzyme, PSMD14, in autophagy [ 7 ], (5) sorting nexins in the UPS, autophagy and endocytosis [ 8 ], (6) ubiquitin and UBL proteins in selective autophagy [ 9 ], as well as (7) structures and interactions of the UBL proteins of Atg8-family [ 13 ].…”

“…All of them are at the intersection of ubiquitin-related processes and autophagy, including the roles of: (1) ATG and UBL proteins in the UPS and autophagy [ 2 , 3 ], (2) ubiquitin-binding autophagic receptor, p62, in autophagy signaling [ 4 ], (3) LC3-interacting region (LIR) of connexins in binding to UBL proteins [ 6 ], (4) proteasomal deubiquitinating enzyme, PSMD14, in autophagy [ 7 ], (5) sorting nexins in the UPS, autophagy and endocytosis [ 8 ], (6) ubiquitin and UBL proteins in selective autophagy [ 9 ], as well as (7) structures and interactions of the UBL proteins of Atg8-family [ 13 ]. In addition to the studies on ubiquitin and autophagy in cell culture, several groups used model organisms, such as laboratory mice [ 1 , 5 ], nematode Caenorhabditis elegans [ 2 ], and social amoeba Dictyostelium discoideum [ 3 ]. Besides, the review article of Ma and colleagues discusses the interplay between the UPS and autophagy in plants [ 10 ].…”

“…Given a complex relationship between the UPS and autophagy that started to be appreciated recently (and was one of the motivations for this Special Issue), it is not surprising that many research articles have a common sub-theme of “UPS-autophagy crosstalk”. For example, Kang et al reported that decreased proteasomal degradation of TonEBP protein under the ER stress conditions in β-cells is responsible for increased autophagosome formation, decreased accumulation of protein aggregates and better cell survival [ 1 ]. However, the decreased cleavage of K63-ubiquitin chains by proteasomal PSMD14 promotes retention of ATG9A and RAB1A proteins in Golgi apparatus and blocks autophagy via the reduced Golgi-to-ER retrograde transport [ 7 ].…”