LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis

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The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death 2-8 . In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype 9-11 . Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1 -/- (also known as Rbck1 -/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3 -/- Casp8 -/- Hoil-1 -/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.


  • Nieves Peltzer
  • Maurice Darding
  • Antonella Montinaro
  • Peter Draber
  • Helena Draberova
  • Sebastian Kupka
  • Eva Rieser
  • Amanda Fisher
  • Ciaran Hutchinson
  • Lucia Taraborrelli
  • Torsten Hartwig
  • Elodie Lafont
  • Tobias L. Haas
  • Yutaka Shimizu
  • Aida Sarr
  • James Rickard
  • Silvia Alvarez-Diaz
  • Michael T. Ashworth
  • Allison Beal
  • John Bertin
  • William Kaiser
  • Andreas Strasser
  • John Silke
  • Philippe Bouillet
  • Henning Walczak
Externa organisationer
  • UCL Cancer Institute
  • University of Manchester
  • Catholic University of the Sacred Heart
  • Walter and Eliza Hall Institute of Medical Research
  • University of Melbourne
  • GlaxoSmithKline

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Sidor (från-till)112-117
Antal sidor6
Utgåva nummer7703
StatusPublished - 2018 maj 3
Peer review utfördJa
Externt publiceradJa