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

• Published in: Cell death & disease 2020-01, Vol.11 (1), p.17-17, Article 17
• Main Authors: Wang, Jianye, Hu, Bian, Zhao, Zhicong, Zhang, Haiyan, Zhang, He, Zhao, Zhenjun, Ma, Xiong, Shen, Bin, Sun, Beicheng, Huang, Xingxu, Hou, Jiajie, Xia, Qiang
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/21; 13/31; 13/89; 14/1; 14/34; 45/77; 631/80; 64/60; 692/699/1503/1607; Activating transcription factor 1; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; CCAAT/enhancer-binding protein; Cell Biology; Cell Culture; Cell death; Cytotoxicity; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Homeostasis; Immunology; Initiation factor eIF-2α; Interleukin 24; Interleukins - deficiency; Interleukins - metabolism; Intracellular Space - metabolism; Life Sciences; Liver; Liver - injuries; Liver - metabolism; Liver - pathology; Liver diseases; Mice, Inbred C57BL; Models, Biological; Protein folding; Proteins; Signal Transduction; Transcription Factor CHOP - metabolism; Unfolded Protein Response; X-Box Binding Protein 1 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2209-6

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 antiapoptotic 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 CCL 4 - or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) 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 eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.