LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
Details
Publication Year 2018-09-25, Volume 9, Issue #1, Page 3910
Journal Title
Nature Communications
Publication Type
Journal Article
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 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.
Publisher
Springer Nature
WEHI Research Division(s)
Molecular Genetics Of Cancer; Cell Signalling And Cell Death
PubMed ID
30254289
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-018-06155-8
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-10-11 04:23:19
Last Modified: 2018-10-12 03:53:38
An error has occurred. This application may no longer respond until reloaded. Reload 🗙