16 research outputs found
Role of translation initiation factor eIF-2B in the regulation of protein synthesis in mammalian cells
Cloning and charaterization of complementary and genomic DNAs encoding the ε-subunit of rat translation initiation factor-2B
Cloning and characterization of cDNAs encoding the ε-subunit of eukaryotic initiation factor-2B from rabbit and human
Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells
Co-ingestion of carbohydrate and whey protein increases fasted rates of muscle protein synthesis immediately after resistance exercise in rats
Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B
Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation. However, despite increased levels of phosphorylated eIF2α (p-eIF2α), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins. As p-eIF2α decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signalling activates eIF2B GEF activity to counteract the effects of p-eIF2α. We now show that TLR-TRIF signalling activates eIF2B GEF through PP2A-mediated serine dephosphorylation of the eIF2B ε-subunit. PP2A itself is activated by decreased Src-family-kinase-induced tyrosine phosphorylation of its catalytic subunit. Each of these processes is required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefiting from the protective arms of the UPR. © 2012 Macmillan Publishers Limited. All rights reserved.link_to_subscribed_fulltex