LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L.
Nat Commun
; 9(1): 3910, 2018 09 25.
Article
em En
| MEDLINE
| ID: mdl-30254289
ABSTRACT
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 HoipE-KO and Hoil-1E-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 ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
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Fator de Necrose Tumoral alfa
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Ubiquitina-Proteína Ligases
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Dermatite
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Proteína Ligante Fas
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Ligante Indutor de Apoptose Relacionado a TNF
Limite:
Animals
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido