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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F18%3A00495757" target="_blank" >RIV/68378050:_____/18:00495757 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1038/s41586-018-0064-8" target="_blank" >http://dx.doi.org/10.1038/s41586-018-0064-8</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41586-018-0064-8" target="_blank" >10.1038/s41586-018-0064-8</a>

Result language

angličtina

Original language name

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

Original language description

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 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30102 - Immunology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature

ISSN

0028-0836

e-ISSN

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Volume of the periodical

557

Issue of the periodical within the volume

7703

Country of publishing house

GB - UNITED KINGDOM

Number of pages

6

Pages from-to

112-117

UT code for WoS article

000431234500040

EID of the result in the Scopus database

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