Abstract
Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation1,2. 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 proteins3. 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 ɛ-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.
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Acknowledgements
This work was supported by postdoctoral fellowship grants from the Canadian Institutes of Health Research and the Heart & Stroke Foundation of Canada (C.W.W.); NIH-NHLBI grants HL75662 and HL57560 (I.T.); and NIH-NIDDK grants DK13499 and DK15658 (S.R.K.). We thank D. Ron (University of Cambridge, UK) for helpful discussions and for providing the CHOP–GFP reporter plasmid; C. Proud (University of Southampton, UK) for recombinant GST–DYRK2; D. Ren (University of Pennsylvania, USA) for advice regarding the use of mutant Src constructs; D. L. Brautigan (University of Virginia School of Medicine, USA) for the construct encoding PP2AcY307F; B. A. Hemmings (Friedrich Miescher Institute, Basel, Switzerland) for the construct encoding PP2AcL199P; and B. Berk (University of Rochester, USA) for an adenoviral vector encoding kinase-inactive Src.
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C.W.W. carried out the experiments and assisted with planning the experiments, data analysis and writing the manuscript; L.K. assisted with planning the experiments and data analysis; S.R.K. assisted with planning the experiments, data analysis and writing the manuscript; I.T. coordinated the project and assisted with planning the experiments, data analysis and writing the manuscript.
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Woo, C., Kutzler, L., Kimball, S. et al. Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. Nat Cell Biol 14, 192–200 (2012). https://doi.org/10.1038/ncb2408
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DOI: https://doi.org/10.1038/ncb2408