HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death
- Author(s)
- Peltzer, N; Rieser, E; Taraborrelli, L; Draber, P; Darding, M; Pernaute, B; Shimizu, Y; Sarr, A; Draberova, H; Montinaro, A; Martinez-Barbera, JP; Silke, J; Rodriguez, TA; Walczak, H;
- Details
- Publication Year 2014-10-01,Volume 9,Issue #1,Page 153-65
- Journal Title
- Cell Rep
- Publication Type
- Journal Article
- Abstract
- Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP. Finally, we show that HOIP's catalytic activity is necessary for preventing TNF-induced cell death. Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death.
- Publisher
- Cell Press
- Research Division(s)
- Cell Signalling And Cell Death
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2014.08.066
- Open Access at Publisher's Site
http://www.sciencedirect.com/science/article/pii/S2211124714007426- Terms of Use/Rights Notice
- This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
Creation Date: 2014-10-13 02:21:53