cIAPs control RIPK1 kinase activity‐dependent and ‐independent cell death and tissue inflammation

Author:

Schorn Fabian1,Werthenbach J Paul1ORCID,Hoffmann Mattes1,Daoud Mila1ORCID,Stachelscheid Johanna1ORCID,Schiffmann Lars M2,Hildebrandt Ximena3ORCID,Lyu Su Ir4ORCID,Peltzer Nieves3,Quaas Alexander4,Vucic Domagoj5ORCID,Silke John6ORCID,Pasparakis Manolis789ORCID,Kashkar Hamid189ORCID

Affiliation:

1. Faculty of Medicine and University Hospital of Cologne, Institute for Molecular Immunology University of Cologne Cologne Germany

2. Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral, Cancer and Transplantation Surgery University of Cologne Cologne Germany

3. Faculty of Medicine and University Hospital of Cologne, Department of Translational Genomics University of Cologne Cologne Germany

4. Faculty of Medicine and University Hospital of Cologne, Institute of Pathology and Center for Integrated Oncology (CIO) Cologne Bonn University of Cologne Cologne Germany

5. Department of Immunology Discovery Genentech South San Francisco CA USA

6. The Walter and Eliza Hall Institute for Medical Research Melbourne Vic. Australia

7. Institute for Genetics University of Cologne Cologne Germany

8. Faculty of Medicine and University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany

9. Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany

Abstract

AbstractCellular 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, cIAP1/2MutR). cIap1/2MutR/MutR mice died during embryonic development due to RIPK1‐mediated apoptosis. While expression of kinase‐inactive RIPK1D138N rescued embryonic development, Ripk1D138N/D138N/cIap1/2MutR/MutR mice developed systemic inflammation and died postweaning. Cells expressing cIAP1/2MutR and RIPK1D138N 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.

Funder

Deutsche Krebshilfe

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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