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

Published on Jun 4, 2019in bioRxiv
· DOI :10.1101/658666
Jianye Wang2
Estimated H-index: 2
(SJTU: Shanghai Jiao Tong University),
Bian Hu (ShanghaiTech University)+ 9 AuthorsQiang Xia21
Estimated H-index: 21
(SJTU: Shanghai Jiao Tong University)
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 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.
  • References (33)
  • Citations (0)
#1Emily E. Fink (Roswell Park Cancer Institute)H-Index: 9
#2Sudha Moparthy (Wake Forest Baptist Medical Center)H-Index: 4
Last.Mikhail A. Nikiforov (Wake Forest Baptist Medical Center)H-Index: 24
view all 13 authors...
#1Cynthia Lebeaupin (French Institute of Health and Medical Research)H-Index: 8
#2Deborah Vallee (French Institute of Health and Medical Research)H-Index: 3
Last.Béatrice Bailly-Maitre (French Institute of Health and Medical Research)H-Index: 19
view all 6 authors...
#1Chang Yeob Han (SNU: Seoul National University)H-Index: 7
#2Sang Woo Lim (SNU: Seoul National University)H-Index: 1
Last.Sang Geon Kim (SNU: Seoul National University)H-Index: 46
view all 5 authors...
#1Michal Kandel-Kfir (Sheba Medical Center)H-Index: 5
#2Tal Almog (Sheba Medical Center)H-Index: 5
Last.Yehuda Kamari (TAU: Tel Aviv University)H-Index: 20
view all 10 authors...
#1Nobuhiko Hiramatsu (UCSD: University of California, San Diego)H-Index: 6
#2Wei-Chieh Chiang (UCSD: University of California, San Diego)H-Index: 10
Last.Jonathan H. Lin (UCSD: University of California, San Diego)H-Index: 24
view all 5 authors...
#1Yang Liu (CAS: Chinese Academy of Sciences)H-Index: 57
#2Mengle Shao (CAS: Chinese Academy of Sciences)H-Index: 18
Last.Yong(刘勇) Liu (CAS: Chinese Academy of Sciences)H-Index: 26
view all 12 authors...
Cited By0
View next paperHepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation