Taraborrelli, Lucia, Peltzer, Nieves ORCID: 0000-0002-4134-5852, Montinaro, Antonella, Kupka, Sebastian, Rieser, Eva, Hartwig, Torsten, Sarr, Aida, Darding, Maurice, Draber, Peter ORCID: 0000-0001-8658-4614, Haas, Tobias L., Akarca, Ayse, Marafioti, Teresa ORCID: 0000-0003-1223-6275, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Bertin, John, Gough, Peter J., Bouillet, Philippe ORCID: 0000-0002-9012-6058, Strasser, Andreas ORCID: 0000-0002-5020-4891, Leverkus, Martin, Silke, John ORCID: 0000-0002-7611-5774 and Walczak, Henning ORCID: 0000-0002-6312-4591 (2018). LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat. Commun., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 ubi-quitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Taraborrelli, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peltzer, NievesUNSPECIFIEDorcid.org/0000-0002-4134-5852UNSPECIFIED
Montinaro, AntonellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kupka, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rieser, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartwig, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarr, AidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darding, MauriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Draber, PeterUNSPECIFIEDorcid.org/0000-0001-8658-4614UNSPECIFIED
Haas, Tobias L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akarca, AyseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marafioti, TeresaUNSPECIFIEDorcid.org/0000-0003-1223-6275UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Bertin, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gough, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouillet, PhilippeUNSPECIFIEDorcid.org/0000-0002-9012-6058UNSPECIFIED
Strasser, AndreasUNSPECIFIEDorcid.org/0000-0002-5020-4891UNSPECIFIED
Leverkus, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silke, JohnUNSPECIFIEDorcid.org/0000-0002-7611-5774UNSPECIFIED
Walczak, HenningUNSPECIFIEDorcid.org/0000-0002-6312-4591UNSPECIFIED
URN: urn:nbn:de:hbz:38-172512
DOI: 10.1038/s41467-018-06155-8
Journal or Publication Title: Nat. Commun.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; CHRONIC PROLIFERATIVE DERMATITIS; INDUCED GENE ACTIVATION; LINEAR UBIQUITIN; DEFICIENCY; INFLAMMATION; CASPASE-8; SHARPIN; RIPK1; MICEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17251

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