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.