HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death Academic Article uri icon

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

  • Peltzer, N
  • Rieser, E
  • Taraborrelli, L
  • Draber, P
  • Darding, M
  • Pernaute, B
  • Shimizu, Y
  • Sarr, A
  • Draberova, H
  • Montinaro, A
  • Martinez-Barbera, J
  • Silke, J
  • Rodriguez, TA
  • Walczak, H

publication date

  • 2014

has subject area