Control of cell fate by the mammalian target of rapamycin (mTOR) under stress depends on eIF2α serine 51 phosphorylation

ABSTRACT The mammalian/mechanist target of rapamycin (mTOR) plays an essential role in cell growth and metabolism by regulating protein and RNA stability, transcription as well as mRNA translation. Phosphorylation of the a subunit of translation initiation factor eIF2 at serine 51 (eIF2aS51P) is a key regulator of mRNA translation and an important determinant of cell fate under stress. Some studies have provided evidence for a cross-talk between mTOR and eIF2aS51P under stress through poorly defined mechanisms. Herein, we demonstrate that genetic as well as pharmacological inhibition of mTOR complex 2 (mTORC2) induces eIF2aS51P via the activation of the endoplasmic reticulum (ER)-resident kinase PERK/PEK as a result of Akt inactivation. Analysis of the functional interplay between eIF2aS51P and mTOR in tuberous sclerosis complex (TSC)-deficient cells showed that mTORC2 inactivation induces the PERK-eIF2aS51P arm to substitute for the loss of Akt and promote survival in response to ER stress (see Figure above). On the other hand, TSC-deficient cells decrease PERK activity and increase the activity of the double-stranded RNA-activated protein kinase PKR to promote death via eIF2aS51P, JNK activation and increased autophagy in response to oxidative stress (see attached Figure). The balance between PERK inactivation and PKR activation in TSC-mutant cells under oxidative stress is controlled by mTORC1 and ribosomal S6 kinase 1, 2 (S6K1, 2) activity. Impaired eIF2aS51P accelerates TSC-mutant tumor initiation in mice, which is associated with an impaired production of reactive oxygen species (ROS) compared to eIF2aS51P-proficient TSC-mutant tumors. Our study reveals that eIF2aS51P acts as a double-edged sword downstream of mTOR to promote either survival or death in response to distinct forms of stress with implications in tumor development and treatment with chemotherapeutic drugs. Download : Download full-size image P5.03 FIGURES .