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

Peltzer, N; Darding, M; Montinaro, A; Draber, P; Draberova, H; Kupka, S; Rieser, E; Fisher, A; Hutchinson, C; Taraborrelli, L; Hartwig, T; Lafont, E; Haas, TL; Shimizu, Y; Boiers, C; Sarr, A; Rickard, J; Alvarez-Diaz, S; Ashworth, MT; Beal, A; Enver, T; Bertin, J; Kaiser, W; Strasser, A; Silke, J; Bouillet, P; Walczak, H

Author(s): Peltzer, N; Darding, M; Montinaro, A; Draber, P; Draberova, H; Kupka, S; Rieser, E; Fisher, A; Hutchinson, C; Taraborrelli, L; Hartwig, T; Lafont, E; Haas, TL; Shimizu, Y; Boiers, C; Sarr, A; Rickard, J; Alvarez-Diaz, S; Ashworth, MT; Beal, A; Enver, T; Bertin, J; Kaiser, W; Strasser, A; Silke, J; Bouillet, P; Walczak, H;
Details: Publication Year 2018-04-25,Volume 557,Issue #7703,Page 112-117
Journal Title: Nature
Publication Type: Journal Article
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 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.
Publisher: Springer Nature
Research Division(s): Molecular Genetics Of Cancer; Cell Signalling And Cell Death
PubMed ID: 29695863
Publisher's Version: https://doi.org/10.1038/s41586-018-0064-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-05-18 09:33:25

Last Modified: 2018-05-31 09:15:16