ATF5 regulates β-cell survival during stress

Abstract

The stress response and cell survival are necessary for normal pancreatic β-cell function, glucose homeostasis, and prevention of diabetes. The homeodomain transcription factor and human diabetes gene pancreas/duodenum homeobox protein 1 (Pdx1) regulates β-cell survival and endoplasmic reticulum stress susceptibility, in part through direct regulation of activating transcription factor 4 (Atf4). Here we show that Atf5, a close but less-studied relative of Atf4, is also a target of Pdx1 and is critical for β-cell survival under stress conditions. Pdx1 deficiency led to decreased Atf5 transcript, and primary islet ChIP-sequencing localized PDX1 to the Atf5 promoter, implicating Atf5 as a PDX1 target. Atf5 expression was stress inducible and enriched in β cells. Importantly, Atf5 deficiency decreased survival under stress conditions. Loss-of-function and chromatin occupancy experiments positioned Atf5 downstream of and parallel to Atf4 in the regulation of eIF4E-binding protein 1 (4ebp1), a mammalian target of rapamycin (mTOR) pathway component that inhibits protein translation. Accordingly, Atf5 deficiency attenuated stress suppression of global translation, likely enhancing the susceptibility of β cells to stress-induced apoptosis. Thus, we identify ATF5 as a member of the transcriptional network governing pancreatic β-cell survival during stress.educed pancreatic β-cell number and function characterize all forms of diabetes. Insulin-secreting β cells are notoriously susceptible to stress, including endoplasmic reticulum (ER), cytokine, and oxidative stress (1-4). Thus, understanding apoptotic cell-fate decisions during stress could provide new targets that could be exploited for the prevention or amelioration of diabetes.In secretory cells such as the β cell, the unfolded protein response (UPR) and regulation of translation, particularly in response to stress, are key factors in maintaining cellular homeostasis, as clearly demonstrated in mouse models with deficiencies of critical regulators such as protein kinase R-like ER kinase (PERK) and EIF2α (5-7). In humans, PERK mutation causes Wolcott-Rallison syndrome, a rare autosomal recessive disorder characterized by permanent neonatal diabetes (8, 9). Downstream of PERK, the basic leucine zipper (bZIP) transcription factor activating transcription factor 4 (ATF4) regulates the expression of 4ebp1, a member of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein family (4EBPs). 4EBP1 is the most abundant mammalian isoform in the pancreas (10) and functions as an inhibitor of translation initiation by binding the capbinding protein eIF4E, thereby preventing formation of the eIF4F translational initiation complex (11,12). Expression of 4EBP1 is induced by stress, and 4ebp1 deficiency results in deregulated translational control and increased susceptibility to ER stressmediated apoptosis in β cells (13).We previously demonstrated that the homeodomain transcription factor and human diabetes gene pancreas/duodenum homeobox protein 1 (Pdx1) regulates p...

The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer

“…ATF5 can then activate transcription of molecular chaperones and proteases which are involved in restoring proteostasis [ 30 , 31 ]. If proteostasis is significantly imbalanced, apoptosis can then be triggered by downregulation of ATF5 [ 25 , 32 ]. It is likely that this prosurvival effect is due to regulation of heat shock proteins and antiapoptotic proteins such as HSP27 [ 31 ], BCL-2 [ 33 ], and MCL-1 [ 34 ], as detailed in the sections below.…”

“…Initially, it was found that ATF5 is a likely downstream target of the transcription factor PDX1, which mediates β-cell susceptibility to ER stress [ 42 ]. Further research by Juliana et al reported that β-cells induced ATF5 expression upon induction of ER stress, and that knockdown of ATF5 made these cells susceptible to ER stress-induced apoptosis via hindered inhibition of global protein translation [ 32 ]. While this is true, the physiological relevance of ATF5 activity to β cell function is unclear since in this study ATF5 knockout mice showed no alteration in their glucose homeostasis phenotype in glucose and insulin tolerance tests.…”

Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting

“…First, eIF2 phosphorylation is increased, which is expected to directly repress cap-dependent protein translation. Secondly, we observed the transcriptional activation of 4EBP1, a target of the ISR network (56). This leads to the accumulation of both non-phosphorylated and phosphorylated forms of the protein, with the former acting as a repressor of protein translation.…”

“…5b & 5c). Interestingly, the transcription of EIF4EBP1 (or 4EBP1), a downstream target of the ISR 23 , is increased ( Fig. 4a).…”

Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

“…The unfolded-protein response (UPR) and oxidative stress response (OSR) are central protectors of cell function and survival (Juliana et al, 2017;Sies et al, 2017). Unfolded proteins in the endoplasmic reticulum (ER) sequester resident chaperones such as GRP78/Bip and stimulate early sensor-effectors of the stress response, including Inositol Requiring 1 (IRE1), Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and Activating Transcription Factor 6 (ATF6) (Cao and Kaufman, 2014).…”