Journal
CELL REPORTS
Volume 9, Issue 1, Pages 153-165Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.08.066
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Funding
- Wellcome Trust Senior Investigator Award [096831/Z/11/Z]
- NHMRC [602516, 294880]
- Swiss National Science Foundation [P2LAP3_148447]
- MRC [MR/K00090X/1] Funding Source: UKRI
- Wellcome Trust [096831/Z/11/Z] Funding Source: Wellcome Trust
- Swiss National Science Foundation (SNF) [P2LAP3_148447] Funding Source: Swiss National Science Foundation (SNF)
- Great Ormond Street Hospital Childrens Charity [W1055] Funding Source: researchfish
- Medical Research Council [MR/K00090X/1] Funding Source: researchfish
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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-a (LT-a), 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.
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