Abstract
Tumor necrosis factor (TNF) is a key signaling molecule orchestrating immune and inflammatory responses and possesses the capacity to trigger apoptotic as well as necroptotic cell death. Apoptotic cell death elicited by TNF has been demonstrated to engage pro-apoptotic Bcl-2 family proteins, most prominently the BH3-only protein Bid, a key substrate of caspase-8, the key effector protease downstream of TNF receptor I. Most recently, the BH3 domain-containing protein Bad (Bcl-2-antagonist of cell death) has been shown to be rate limiting for TNF-mediated cell death, suggesting possible synergy with Bid, but genetic analyses presented here demonstrate that it is dispensable for this process.
Highlights
Recent studies define a delicate network of linear and branched ubiquitylation/deubiquitylation-controlled signaling events downstream of TNF receptor I (TNFRI) as critical for the decision between life and death upon Tumor necrosis factor (TNF) stimulation.[3,4] Its pro-death function is thereby constrained by different means but most prominently by NF-κB-dependent transcription of survival genes, such as Bcl-x, XIAP (X-linked inhibitor of apoptosis protein), cIAPs or c-FLIP, a dimerization and activation partner of procaspase-8 that is rate limiting for TNF-driven apoptosis and prevents RIPK1/RIPK3-dependent necroptosis that can ensue when caspase-8 is inhibited.[5]
This study showed that mouse embryonic fibroblasts (MEFs), derived from Ikbkb−/− mice, that are deficient in IKKβ/IKK2, where Bad expression was repressed by RNA interference, or MEFs from Bad−/− mice that were pre-treated with the IKK inhibitor PS-1145, showed reduced caspase-3/7 activity, delayed PARP cleavage and strongly reduced cell death upon TNF treatment
We conclude that Bad does not contribute to spontaneous or TNF-mediated cell death in thymocytes, neither under steady state conditions, in line with the initial reports by Ranger et al.,[10] nor upon inhibition of the IKK complex
Summary
Recent studies define a delicate network of linear and branched ubiquitylation/deubiquitylation-controlled signaling events downstream of TNFRI as critical for the decision between life and death upon TNF stimulation.[3,4] Its pro-death function is thereby constrained by different means but most prominently by NF-κB-dependent transcription of survival genes, such as Bcl-x, XIAP (X-linked inhibitor of apoptosis protein), cIAPs (inhibitor of apoptosis proteins) or c-FLIP (cellular FLICE inhibitory protein), a dimerization and activation partner of procaspase-8 that is rate limiting for TNF-driven apoptosis and prevents RIPK1/RIPK3-dependent necroptosis that can ensue when caspase-8 is inhibited.[5]. On the other hand, appears to be controlled by TNF-driven JNK-mediated phosphorylation and both, Bid and Bim, contribute to T-celldriven TNF-dependent liver toxicity.[6] TNF has been shown to trigger NF-κB-dependent transcriptional activation of Puma and deficiency of this BH3-only protein can provide protection from hepatocyte killing upon systemic TNF administration.[7] Together these findings show that mitochondrial apoptosis, controlled by the Bcl-2 family, can be a critical event in pathological hepatocyte cell death in response to TNF. Bad-deficient animals were protected from the lethal effects of hepatitis elicited by D-GalN priming and subsequent TNF injection Together, these data provided a strong evidence for an NF-κB-independent anti-apoptotic function of the IKK complex, explaining, at least in part, the increased cell death susceptibility of IKKβ-deficient MEF over those lacking the NF-κB family members RelA plus cRel[9] and supported a rate-limiting role of Bad in TNF-induced cell death signaling. Intrigued by an earlier report describing the generation and phenotype of Bad−/− mice that reported normal cell death responses upon TNF treatment,[10] we decided to reinvestigate
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