1. Academic Validation
  2. Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1

Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1

  • Cell Death Differ. 2022 Jun;29(6):1176-1186. doi: 10.1038/s41418-021-00908-7.
Yiming Hu  # 1 2 Haohao Zhang  # 1 2 Ningxia Xie 1 Dandan Liu 1 2 Yuhang Jiang 1 2 Zhi Liu 1 2 Deji Ye 1 2 Sanhong Liu 3 Xi Chen 2 Cuifeng Li 1 2 Qi Wang 1 2 Xingxu Huang 1 Yongzhong Liu 4 Yufang Shi 2 Xiaoren Zhang 5 6
Affiliations

Affiliations

  • 1 Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  • 3 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China.
  • 5 Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China. [email protected].
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China. [email protected].
  • # Contributed equally.
Abstract

Tumor necrosis factor-α (TNF) is described as a main regulator of cell survival and Apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced Apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced Apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the Deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the Caspase cascade to induce Apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related Apoptosis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15518
    99.91%, IAP Inhibitor
    IAP