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 death2,3,4,5,6,7,8. 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 phenotype9,10,11. 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.
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V. Dixit and K. Newton provided Ripk3−/− mice, S. Hedrick and R. Hakem provided Casp8fl/fl mice; H. Anderton and U. Nachbur helped with Sharpincpdm analysis; P. Levy and staff and L. Lawrence provided technical and histology services. A. Leister and J. Marinis advised on GSK’457A. T. Marafioti and A. Akarsa helped with phosphorylated MLKL detection. A. Annibaldi provided scientific advice and helpful discussions. B. J. Ferguson provided reagents and advice. The flow cytometry, microscopy and imaging core facilities are supported by Cancer Research UK through the CRUK-UCL Centre (515818) and a Cancer Immunotherapy Accelerator award (CITA, 525877). This work was funded by a Wellcome Trust Senior Investigator Award (096831/Z/11/Z), an ERC Advanced grant (294880) and a Cancer Research UK programme grant (A17341) awarded to H.W., NHMRC grants awarded to P.B., A. St., J.S. and H.W. (602516, 1037321, 1043414, 1080321, 1105209, 461221, 1042629, 1057905), the Leukemia and Lymphoma Society (Specialised Center of Research grant 7015) and a postdoctoral fellowship awarded to N.P. by the Swiss National Science Foundation (P300P3_158509).
Nature thanks F. Chan and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Nature Communications (2018)