Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression

Abstract

Activation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse cellular processes, including those involved in cytokine signaling. Using expression of the IL-4/IL-13 receptor subunit Il4ra as a sentinel, we sought to understand the mechanism behind this suppression and its impact on inflammatory signaling. We found that reinitiation of global protein synthesis by GADD34-mediated dephosphorylation of eIF2α resulted in preferential expression of the inhibitory LIP isoform of the transcription factor C/EBPβ. This regulation was in turn required for the suppression of Il4ra and related inflammatory genes. Suppression of Il4ra was lost in Cebpb-/- cells but could be induced by LIP overexpression. As a consequence of Il4ra suppression, ER stress impaired IL-4/IL-13 signaling. Strikingly, Cebpb-/- cells lacking Il4ra downregulation were protected from this signaling impairment. This work identifies a novel role for C/EBPβ in regulating transcriptional suppression and inflammatory signaling during ER stress.