LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

Lucia Taraborrelli, Nieves Peltzer, Antonella Montinaro, Sebastian Kupka, Eva Rieser, Torsten Hartwig, Aida Sarr, Maurice Darding, Peter Draber, Tobias L. Haas, Ayse Akarca, Teresa Marafioti, Manolis Pasparakis, John Bertin, Peter J. Gough, Philippe Bouillet, Andreas Strasser, Martin Leverkus, John Silke and Henning Walczak ()
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Lucia Taraborrelli: University College London
Nieves Peltzer: University College London
Antonella Montinaro: University College London
Sebastian Kupka: University College London
Eva Rieser: University College London
Torsten Hartwig: University College London
Aida Sarr: University College London
Maurice Darding: University College London
Peter Draber: University College London
Tobias L. Haas: Università Cattolica del Sacro Cuore
Ayse Akarca: University College London
Teresa Marafioti: University College London
Manolis Pasparakis: University of Cologne
John Bertin: GlaxoSmithKline
Peter J. Gough: GlaxoSmithKline
Philippe Bouillet: The Walter and Eliza Hall Institute of Medical Research
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
Martin Leverkus: University Hospital of RWTH Aachen University
John Silke: The Walter and Eliza Hall Institute of Medical Research
Henning Walczak: University College London

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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 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.

Date: 2018
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DOI: 10.1038/s41467-018-06155-8

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