LUBAC is essential for embryogenesis by preventing cell death and enabling 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, Charlotta Böiers, Aida Sarr, James Rickard, Silvia Alvarez-Diaz, Michael T. Ashworth, Allison Beal, Tariq Enver, John Bertin, William Kaiser, Andreas Strasser, John Silke, Philippe Bouillet and Henning Walczak ()
Additional contact information
Nieves Peltzer: University College London
Maurice Darding: University College London
Antonella Montinaro: University College London
Peter Draber: University College London
Helena Draberova: University College London
Sebastian Kupka: University College London
Eva Rieser: University College London
Amanda Fisher: University of Texas Health Science Center
Ciaran Hutchinson: UCL Great Ormond Street Institute of Child Health
Lucia Taraborrelli: University College London
Torsten Hartwig: University College London
Elodie Lafont: University College London
Tobias L. Haas: Università Cattolica del Sacro Cuore
Yutaka Shimizu: University College London
Charlotta Böiers: University College London
Aida Sarr: University College London
James Rickard: The Walter and Eliza Hall Institute of Medical Research
Silvia Alvarez-Diaz: The Walter and Eliza Hall Institute of Medical Research
Michael T. Ashworth: UCL Great Ormond Street Institute of Child Health
Allison Beal: Immuno-Inflammation Therapeutic Area, GlaxoSmithKline
Tariq Enver: University College London
John Bertin: Immuno-Inflammation Therapeutic Area, GlaxoSmithKline
William Kaiser: University of Texas Health Science Center
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
John Silke: The Walter and Eliza Hall Institute of Medical Research
Philippe Bouillet: The Walter and Eliza Hall Institute of Medical Research
Henning Walczak: University College London

Nature, 2018, vol. 557, issue 7703, 112-117

Abstract: Abstract The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR11. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0064-8

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