Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06155-8
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Funding
- Wellcome Trust [096831/Z/11/Z]
- ERC [294880]
- NHMRC [602516, 1113133, 1042629, 1107149, 1020363]
- Swiss National Science Foundation [P300P3_158509]
- Swiss National Science Foundation (SNF) [P300P3_158509] Funding Source: Swiss National Science Foundation (SNF)
- National Health and Medical Research Council of Australia [1107149] Funding Source: NHMRC
- European Research Council (ERC) [294880] Funding Source: European Research Council (ERC)
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The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in Hoip(E-KO) and Hoil-1(E-KO) mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubi-quitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.
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