Journal
CELL DEATH AND DIFFERENTIATION
Volume 29, Issue 6, Pages 1176-1186Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00908-7
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Funding
- National Key R&D Program of China [2018YFA0107500, 2021YFA0804703]
- National Natural Science Foundation of China [91949102, 91742113, 31570902, 81771752, 31370881]
- Natural Science Foundation of Shanghai [18ZR1424400, 18ZR1446400, 18431902700]
- Guangzhou Key Medical Discipline Construction Project Fund
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The study demonstrates the crucial role of Bcl-3 in regulating TNF-induced hepatic cell death, with its deficiency protecting mice against hepatoxicity. Bcl-3 interacts with the deubiquitinase CYLD to facilitate the formation of death-inducing Complex II, leading to caspase cascade activation for apoptosis induction.
Tumor necrosis factor-alpha (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 I kappa B 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.
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