HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death
Nieves Peltzer,
Eva Rieser,
Lucia Taraborrelli,
Peter Draber,
Maurice Darding,
Barbara Pernaute,
Yutaka Shimizu,
Aida Sarr,
Helena Draberova,
Antonella Montinaro,
Juan Pedro Martinez-Barbera,
John Silke,
Tristan A. Rodriguez,
Henning Walczak
Affiliations
Nieves Peltzer
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Eva Rieser
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Lucia Taraborrelli
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Peter Draber
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Maurice Darding
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Barbara Pernaute
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
Yutaka Shimizu
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Aida Sarr
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Helena Draberova
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Antonella Montinaro
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
Juan Pedro Martinez-Barbera
Birth Defects Research Centre, Developmental Biology and Cancer Programme, UCL Institute of Child Health, London WC1N 1EH, UK
John Silke
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia
Tristan A. Rodriguez
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
Henning Walczak
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK; Corresponding author
Summary: 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. : HOIP is the main catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), a crucial regulator of TNF and other immune signaling pathways. Peltzer et al. find that HOIP deficiency results in embryonic lethality at midgestation due to endothelial cell death mediated by TNFR1. Aberrant formation of a TNF-mediated cell-death-inducing complex in HOIP-deficient (but not -proficient) cells underlies the phenotype, with the catalytic activity of HOIP required for the control of cell death in response to TNF.
