Toll-like receptor activation suppresses endoplasmic reticulum stress-induced 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(1,2). However, despite increased p-eIF2α, a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis, and translational suppression of critical proteins(3). Because p-eIF2α decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signaling activates eIF2B-GEF activity to counteract the effects of p-eIF2α. We now show that TLR-TRIF signaling activates eIF2B-GEF through PP2A-mediated Ser-dephosphorylation of the eIF2B ε-subunit. PP2A itself is activated by decreased Src-family-kinase-induced Tyr-phosphorylation of its catalytic subunit. Each of these processes are 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 benefitting from the protective arms of the UPR.