LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis Academic Article uri icon


  • 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 death2-8. 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 phenotype9-11. 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.


  • Peltzer, Nieves
  • Darding, Maurice
  • Montinaro, Antonella
  • Draber, Peter
  • Draberova, Helena
  • Kupka, Sebastian
  • Rieser, Eva
  • Fisher, Amanda
  • Hutchinson, Ciaran
  • Taraborrelli, Lucia
  • Hartwig, Torsten
  • Lafont, Elodie
  • Haas, Tobias L
  • Shimizu, Yutaka
  • Böiers, Charlotta
  • Sarr, Aida
  • Rickard, James
  • Alvarez Diaz, Silvia
  • Ashworth, Michael T
  • Beal, Allison
  • Enver, Tariq
  • Bertin, John
  • Kaiser, William
  • Strasser, Andreas
  • Silke, John
  • Bouillet, Philippe
  • Walczak, Henning

publication date

  • 2018

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