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

• Published in: Nature (London) Vol. 557; no. 7703; pp. 112 - 117
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13; 13/1; 13/2; 13/21; 13/31; 13/51; 14; 14/1; 14/34; 14/63; 38; 38/91; 42; 45; 631/136/2086; 631/250/232/1473; 631/80/458/582; 631/80/82; 64; 64/60; 82; 82/1; Animals; Apoptosis; Assembly; Autoimmune diseases; Autoimmunity; Biochemistry; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-8; Cell activation; Cell death; Cell Death - genetics; Clonal deletion; Defects; Deregulation; Disease; Embryo Loss - genetics; Embryogenesis; Embryonic development; Embryonic Development - genetics; Embryonic growth stage; Embryos; Endothelial cells; Endothelial Cells - cytology; Endothelium; Female; Fetuses; Gestation; Health aspects; Hematopoiesis; Hematopoiesis - genetics; Humanities and Social Sciences; Inflammation; Kinases; Lethality; Letter; Ligases; Mice; Mice, Inbred C57BL; Mortality; multidisciplinary; Mutation; Phenotypes; Physiological aspects; Prevention; Protein Domains; Protein Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - deficiency; Receptors; Receptors, Tumor Necrosis Factor, Type I - metabolism; Recruitment; Science; Science (multidisciplinary); Signal Transduction; Trends; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0064-8

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. The HOIL-1 component of the LUBAC ubiquitin ligase complex is required for LUBAC activity, which prevents lethality during embryogenesis by preventing aberrant TNFR1-mediated endothelial cell death and RIPK1-mediated defects in haematopoiesis.