Abstract
Endoplasmic reticulum (ER) stress can be caused by perturbations in ER function resulting from the accumulation of unfolded/misfolded proteins in the ER lumen. Accumulating unfolded proteins trigger unfolded protein responses (UPRs) through activating three transmembrane sensors on the ER: IRE1α, PERK, and ATF6. The orchestrated action of these molecules upregulates genes encoding proteins involved in the downregulation of protein synthesis and acceleration of protein secretion. Ineffectiveness of these fail-safe mechanisms may lead to apoptosis. However, the molecular mechanisms upstream of the UPR are not fully understood. Here we show participation of ataxia telangiectasia mutated (ATM) in stress-induced apoptosis. Cytoplasmic ATM serves as a platform on which protein phosphatase 2A-dependent dephosphorylation of AKT activates glycogen synthase kinase 3β, thereby downregulating nascent polypeptide-associated complex α subunit and γ-taxilin, triggering UPRs and leading to mitochondria-dependent apoptosis. These results suggest an ATM/AKT-dependent cell death pathway triggered by various forms of stress.
Highlights
Endoplasmic reticulum (ER) stress can be caused by perturbations in ER function resulting from the accumulation of unfolded/misfolded proteins in the ER lumen
Excess accumulation of unfolded or misfolded proteins in the ER lumen sequesters binding immunoglobulin protein (BiP) away from the lumenal domains of the ER sensors, freeing the sensors to be activated through homodimerization and autophosphorylation (IRE1α and PERK), or translocation from the ER to the Golgi apparatus followed by protease-mediated fragmentation (AFT6), thereby relaying the signals to the downstream unfolded protein response (UPR) pathways to alleviate the stress by facilitating the excretion of or inhibiting the synthesis of the excess proteins[3]
Cytoplasmic ataxia telangiectasia mutated (ATM) protein acts like a platform, where protein phosphatase 2A (PP2A) mediates dephosphorylation of AKT, thereby relaying the signals downwards to the glycogen synthase kinase 3β (GSK3β)-αNAC/γTX axis and leading to mitochondria-dependent apoptosis in response to various forms of stress
Summary
Endoplasmic reticulum (ER) stress can be caused by perturbations in ER function resulting from the accumulation of unfolded/misfolded proteins in the ER lumen. Cytoplasmic ATM serves as a platform on which protein phosphatase 2A-dependent dephosphorylation of AKT activates glycogen synthase kinase 3β, thereby downregulating nascent polypeptide-associated complex α subunit and γ-taxilin, triggering UPRs and leading to mitochondria-dependent apoptosis. These results suggest an ATM/AKT-dependent cell death pathway triggered by various forms of stress. We provide the evidence that cytoplasmic ataxia telangiectasia mutated (ATM) protein is involved in stress-induced signal transduction responses In this pathway, cytoplasmic ATM protein acts like a platform, where protein phosphatase 2A (PP2A) mediates dephosphorylation of AKT, thereby relaying the signals downwards to the GSK3β-αNAC/γTX axis and leading to mitochondria-dependent apoptosis in response to various forms of stress
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