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Nature. 2018 May;557(7703):112-117. doi: 10.1038/s41586-018-0064-8. Epub 2018 Apr 25.

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

Author information

1
UCL Cancer Institute, University College London, London, UK.
2
Laboratory of Adaptive Immunity, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
3
University of Texas Health Science Center, San Antonio, TX, USA.
4
UCL Great Ormond Street Institute of Child Health, London, UK.
5
Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
6
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
7
Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
8
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
9
UCL Cancer Institute, University College London, London, UK. h.walczak@ucl.ac.uk.

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 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.

PMID:
29695863
PMCID:
PMC5947819
DOI:
10.1038/s41586-018-0064-8
[Indexed for MEDLINE]
Free PMC Article

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