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 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.
Department of Medicine, Columbia University, New York 10032, USA.
Connie W
CW
Woo
Lydia
L
Kutzler
Scot R
SR
Kimball
Ira
I
Tabas
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034622:RNA Interference; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D020717:Eukaryotic Initiation Factor-2B; D008070:Lipopolysaccharides; D054648:Protein Phosphatase 2; D012694:Serine; D051197:Toll-Like Receptor 4; D051742:Transcription Factor CHOP; D014415:Tunicamycin; D019061:src-Family Kinases; C476286:Ticam1 protein, mouse