| First Author | Schorn F | Year | 2023 |
| Journal | EMBO J | Volume | 42 |
| Issue | 22 | Pages | e113614 |
| PubMed ID | 37789765 | Mgi Jnum | J:342656 |
| Mgi Id | MGI:7550308 | Doi | 10.15252/embj.2023113614 |
| Citation | Schorn F, et al. (2023) cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation. EMBO J 42(22):e113614 |
| abstractText | 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. |
