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.
Highlights
Enhanced apoptosis of hepatocytes is a typical feature of various liver diseases, such as drug or toxicant-induced injury, viral hepatitis, cholestasis, ischaemia/reperfusion, and liver preservation for transplantation [1,2,3,4]
Tumor necrosis factor-α (TNF)-induced cytotoxicity has been implicated in various liver diseases, including alcoholic liver disease and chronic viral hepatitis, as well as acute liver injury [35]
In this study we found that B-cell lymphoma 3 (Bcl-3) promotes TNF-induced hepatocyte apoptosis by enhanced receptor interacting protein 1 (RIP1) deubiquitination, providing a novel Bcl-3targeted strategy for various liver diseases
Summary
Enhanced apoptosis of hepatocytes is a typical feature of various liver diseases, such as drug or toxicant-induced injury, viral hepatitis, cholestasis, ischaemia/reperfusion, and liver preservation for transplantation [1,2,3,4]. Accumulating evidence has shown that hepatic apoptosis is modulated by a complicated network of apoptotic and inflammatory signals, which are mainly initiated by tumor necrosis factor receptor (TNFR) family members [5, 6], but the underlying mechanism is still largely unknown. Upon Complex I formation, TNFR1 facilitates the recruitment of TNFR1-associated death domain, TNFR-associated factor 2/5 (TRAF2/5), receptor interacting protein 1 (RIP1) and cellular inhibitor of apoptosis protein 1/2 (cIAP1/2) [11, 12]. This recruitment is crucial for activating NF-κB, JNK and p38 cascades [13,14,15] and further promoting the transcription of pro-survival genes. Many factors that regulate RIP1 ubiquitination have been revealed, with cIAPs, A20 and CYLD as the primary factors [19,20,21]
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