Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of elF2B

Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation(1,2). However,despite increased levels of phosphorylated elF2 alpha (p-elF2 alpha), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins(3). As p-elF2 alpha decreases the functional interaction of elF2 with elF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signalling activates elF2B GEF activity to counteract the effects of p-elF2 alpha. We now show that TLR-TRIF signalling activates elF2B GEF through PP2A-mediated serine dephosphorylation of the elF2B epsilon-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.