Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through ac

Abstract

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response inhibits de novo protein translation and activates CHOP. However, the long-term induction of these pathways in response to prolonged ER stress would be detrimental. Tabas and colleagues now reveal a mechanism through which Toll-like receptor signalling suppresses CHOP activation and promotes protein translation, thus allowing cells to adapt to persistent ER stress. 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.

Cite this article

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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