LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
| Autor: | Ayse U. Akarca, Sebastian Kupka, Andreas Strasser, Nieves Peltzer, Eva Rieser, Tobias L. Haas, Torsten Hartwig, Lucia Taraborrelli, Manolis Pasparakis, Martin Leverkus, Philippe Bouillet, Peter Draber, John Silke, Maurice Darding, Henning Walczak, Peter J. Gough, Teresa Marafioti, Aida Sarr, Antonella Montinaro, John Bertin |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Genetics and Molecular Biology (all)
0301 basic medicine Keratinocytes Programmed cell death Fas Ligand Protein Science Necroptosis Ubiquitin-Protein Ligases General Physics and Astronomy Dermatitis Mice Transgenic Caspase 8 Biochemistry General Biochemistry Genetics and Molecular Biology TNF-Related Apoptosis-Inducing Ligand Physics and Astronomy (all) 03 medical and health sciences RIPK1 Medicine Animals Kinase activity lcsh:Science Receptor Cells Cultured Skin Mice Knockout Settore MED/06 - ONCOLOGIA MEDICA Multidisciplinary Cell Death business.industry Tumor Necrosis Factor-alpha Chemistry (all) Intracellular Signaling Peptides and Proteins General Chemistry 3. Good health Mice Inbred C57BL 030104 developmental biology Animals Newborn Apoptosis Cancer research lcsh:Q Tumor necrosis factor alpha Biochemistry Genetics and Molecular Biology (all) business Carrier Proteins |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-12 (2018) Nature Communications 9, 3910 (2018). doi:10.1038/s41467-018-06155-8 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-06155-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|