Mechanobiology June 26th - June 2nd 2016

Mechanobiology: June 26th  - June 2nd 2016

Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression
Angela M. Arensdorf, D. Thomas Rutkowski


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.


  • Author contributions

    The experiments were conceived and designed by A.M.A. and D.T.R.; A.M.A. conducted the experiments. A.M.A. and D.T.R. analyzed all data and prepared the manuscript.

  • Funding

    This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases [grant number R01 DK084058 to D.T.R.]. Deposited in PMC for release after 12 months.

  • Supplementary material available online at

  • Accepted May 23, 2013.
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