The integrated stress response (ISR) integrates a broad range of environmental and endogenous stress signals to the phosphorylation of the ␣-subunit of eukaryotic translation initiation factor 2 (eIF2␣). Although intense or prolonged activation of this pathway is known to induce apoptosis, the molecular mechanisms coupling stress-induced eIF2␣ phosphorylation to the cell death machinery have remained incompletely understood. In this study, we characterized apoptosis initiation in response to classical activators of the ISR (tunicamycin, UVC, elevated osmotic pressure, arsenite). We found that all applied stress stimuli activated a mitochondrial pathway of apoptosis initiation. Rapid and selective down-regulation of the anti-apoptotic BCL-2 family protein MCL-1 preceded the activation of BAX, BAK, and caspases. Stabilization of MCL-1 blocked apoptosis initiation, while cells with reduced MCL-1 protein content were strongly sensitized to stress-induced apoptosis. Stress-induced elimination of MCL-1 occurred with unchanged protein turnover and independently of MCL-1 mRNA levels. In contrast, stress-induced phosphorylation of eIF2␣ at Ser 51 was both essential and sufficient for the down-regulation of MCL-1 protein in stressed cells. These findings indicate that stress-induced phosphorylation of eIF2␣ is directly coupled to mitochondrial apoptosis regulation via translational repression of MCL-1. Down-regulation of MCL-1 enables but not enforces apoptosis initiation in stressed cells. The integrated stress response (ISR)2 is a general stress response program conserved from yeast to mammals, that is known to integrate various types of environmental and endogenous stress signals, including endoplasmic reticulum stress, amino acid deprivation, infection with double-stranded RNA viruses, osmotic stress, UV light exposure, heme deficiency, and oxidative stress (1-4). Those diverse signals activate specific stress kinases, each of which converges on the phosphorylation at Ser 51 on the ␣-subunit of eukaryotic translation initiation factor 2 (eIF2␣) (1). Phosphorylation of eIF2␣ at Ser 51 abrogates the function of eIF2␣, required for the transfer of the initiator Met-tRNA iMet to the small ribosomal subunit. This leads to a shutdown of global mRNA translation due to reduced AUG initiator codon recognition, along with increased translation of a few selected mRNAs including ATF-4, a basic zipper transcription activator (5-7). As a consequence of global translational arrest, the steady-state levels of most cellular proteins decrease with time, dependent on their respective protein halflife. This has recently been found to be essential for NF-B activation mediated by down-regulation of IB proteins in response to eIF2␣ phosphorylation (8 -10). These findings provide a first striking example of a signaling pathway activated by translational repression of a labile protein during eIF2␣ phosphorylation. Activation of the ISR also mobilizes stress-induced gene expression induced by ATF4 and its target genes, involved in cell growth,...

IkBβ forms a complex with the NF-κB subunits RelA and c-Rel that inhibits the transcription of IL-1β and other genes. Mice lacking IkBβ are protected against LPS-induced shock.

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Herein, we fabricated biocompatible ultrafine fibers based on talc nanosheets (TNS)/PVDF composites that can exhibit robust electromechanical responses. Piezoresponse force microscopy (PFM) was extensively used to decode various characteristics, including ferroelectric and piezoelectric coefficients. The 0.5 wt% TNS dispersed ultrafine fibers exhibited well‐defined ferroelectric characteristics with an enhanced piezoelectric coefficient (d33) of ≈43.3 pm/V compared to 10 pm/V measured for the pristine PVDF ultrafine fibers. It was observed that the piezoelectric coefficient values strongly depended on the morphology and electroactive phase fraction of the ensuing composite ultrafine fiber. The advantage of a high aspect ratio and surface charges offered by TNS alongside electrospinning augmented the composite ultrafine fiber's piezoelectric response. Further, in‐vitro cytotoxicity of the TNS/PVDF composite ultrafine fibers was examined using BALB/3T3 fibroblasts based on ISO Standard 10993‐5. Importantly, the new composite fibers showed no cytotoxic response and the exposed fibroblasts showed excellent viability. Thus, these fabricated TNS/PVDF piezoelectric ultrafine fibers are well suited for applications in bioelectronics, especially as flexible wearable electronic devices, including sensors.