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bioRxiv · 10.1101/658666

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Wang, J.·Hu, B.·Zhao, Z.·Zhang, H.·Ma, X.·Shen, B.·Sun, B.·Huang, X.·Hou, J.·Xia, Q.
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Abstract

Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2 (eIF2) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

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Wang, J., Hu, B., Zhao, Z., Zhang, H., Ma, X., Shen, B., Sun, B., Huang, X., Hou, J., Xia, Q.. 2019-06-04. Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver. https://doi.org/10.1101/658666

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