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HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death.
- Source :
-
Cell reports [Cell Rep] 2014 Oct 09; Vol. 9 (1), pp. 153-165. Date of Electronic Publication: 2014 Oct 02. - Publication Year :
- 2014
-
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-α (LT-α), 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.<br /> (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis physiology
Cell Death physiology
Embryo Loss genetics
Embryo, Mammalian
Endothelial Cells metabolism
Female
Lymphotoxin-alpha pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mitogen-Activated Protein Kinases metabolism
NF-kappa B metabolism
Receptors, Tumor Necrosis Factor, Type I genetics
Tumor Necrosis Factor-alpha pharmacology
Ubiquitin metabolism
Ubiquitin-Protein Ligases genetics
Ubiquitin-Protein Ligases metabolism
Ubiquitination
Yolk Sac blood supply
Embryo Loss metabolism
Endothelial Cells cytology
Receptors, Tumor Necrosis Factor, Type I metabolism
Ubiquitin-Protein Ligases deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 25284787
- Full Text :
- https://doi.org/10.1016/j.celrep.2014.08.066