cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation
- Author(s)
- Schorn, F; Werthenbach, JP; Hoffmann, M; Daoud, M; Stachelscheid, J; Schiffmann, LM; Hildebrandt, X; Lyu, SI; Peltzer, N; Quaas, A; Vucic, D; Silke, J; Pasparakis, M; Kashkar, H;
- Journal Title
- EMBO Journal
- Abstract
- Cellular inhibitor of apoptosis proteins (cIAPs) are RING-containing E3 ubiquitin ligases that ubiquitylate receptor-interacting protein kinase 1 (RIPK1) to regulate TNF signalling. Here, we established mice simultaneously expressing enzymatically inactive cIAP1/2 variants, bearing mutations in the RING domains of cIAP1/2 (cIAP1/2 mutant RING, cIAP1/2(MutR) ). cIap1/2(MutR/MutR) mice died during embryonic development due to RIPK1-mediated apoptosis. While expression of kinase-inactive RIPK1(D138N) rescued embryonic development, Ripk1(D138N/D138N) /cIap1/2(MutR/MutR) mice developed systemic inflammation and died postweaning. Cells expressing cIAP1/2(MutR) and RIPK1(D138N) were still susceptible to TNF-induced apoptosis and necroptosis, implying additional kinase-independent RIPK1 activities in regulating TNF signalling. Although further ablation of Ripk3 did not lead to any phenotypic improvement, Tnfr1 gene knock-out prevented early onset of systemic inflammation and premature mortality, indicating that cIAPs control TNFR1-mediated toxicity independent of RIPK1 and RIPK3. Beyond providing novel molecular insights into TNF-signalling, the mouse model established in this study can serve as a useful tool to further evaluate ongoing therapeutic protocols using inhibitors of TNF, cIAPs and RIPK1.
- Publisher
- EMBO Press
- Keywords
- Ripk1; Tnf; cIAP1; cIAP2; ubiquitin
- Research Division(s)
- Inflammation
- PubMed ID
- 37789765
- Publisher's Version
- https://doi.org/10.15252/embj.2023113614
- Open Access at Publisher's Site
https://doi.org/10.15252/embj.2023113614- Terms of Use/Rights Notice
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Creation Date: 2023-11-20 12:03:37
Last Modified: 2023-11-20 12:12:22