LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L.

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 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 dea

SUBMITTER: Taraborrelli L 

PROVIDER: S-EPMC6156229 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature