Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Taraborrelli, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Peltzer, Nieves UNSPECIFIED orcid.org/0000-0002-4134-5852 UNSPECIFIED Montinaro, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED Kupka, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rieser, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartwig, Torsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Sarr, Aida UNSPECIFIED UNSPECIFIED UNSPECIFIED Darding, Maurice UNSPECIFIED UNSPECIFIED UNSPECIFIED Draber, Peter UNSPECIFIED orcid.org/0000-0001-8658-4614 UNSPECIFIED Haas, Tobias L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Akarca, Ayse UNSPECIFIED UNSPECIFIED UNSPECIFIED Marafioti, Teresa UNSPECIFIED orcid.org/0000-0003-1223-6275 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Bertin, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Gough, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bouillet, Philippe UNSPECIFIED orcid.org/0000-0002-9012-6058 UNSPECIFIED Strasser, Andreas UNSPECIFIED orcid.org/0000-0002-5020-4891 UNSPECIFIED Leverkus, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Silke, John UNSPECIFIED orcid.org/0000-0002-7611-5774 UNSPECIFIED Walczak, Henning UNSPECIFIED orcid.org/0000-0002-6312-4591 UNSPECIFIED
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:	Keywords Language NF-KAPPA-B; CHRONIC PROLIFERATIVE DERMATITIS; INDUCED GENE ACTIVATION; LINEAR UBIQUITIN; DEFICIENCY; INFLAMMATION; CASPASE-8; SHARPIN; RIPK1; MICE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17251