LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
- Author(s)
- Taraborrelli, L; Peltzer, N; Montinaro, A; Kupka, S; Rieser, E; Hartwig, T; Sarr, A; Darding, M; Draber, P; Haas, TL; Akarca, A; Marafioti, T; Pasparakis, M; Bertin, J; Gough, PJ; Bouillet, P; Strasser, A; Leverkus, M; Silke, J; Walczak, H;
- 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
- Research Division(s)
- Molecular Genetics Of Cancer; Cell Signalling And Cell Death
- PubMed ID
- 30254289
- Publisher's Version
- https://doi.org/10.1038/s41467-018-06155-8
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-018-06155-8- NHMRC Grants
- NHMRC/1113133, NHMRC/1042629, NHMRC/1107149, NHMRC/1020363, NHMRC/602516,
- Terms of Use/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