title: HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death.
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.
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Nieves
authors.initials: N
authors.lastname: Peltzer
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Rieser
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Maurice
authors.initials: M
authors.lastname: Darding
authors.affiliation: British Heart Foundation Centre for Research Excellence, National Heart and Lung Institute (NHLI), Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pernaute
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Aida
authors.initials: A
authors.lastname: Sarr
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Draberova
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Montinaro
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.affiliation: British Heart Foundation Centre for Research Excellence, National Heart and Lung Institute (NHLI), Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Tristan A
authors.initials: TA
authors.lastname: Rodriguez
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D015017:Yolk Sac / Q000098:blood supply
chemical_list: D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C492590:Rnf31 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020928:Mitogen-Activated Protein Kinases