Journal article
LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
L Taraborrelli, N Peltzer, A Montinaro, S Kupka, E Rieser, T Hartwig, A Sarr, M Darding, P Draber, TL Haas, A Akarca, T Marafioti, M Pasparakis, J Bertin, PJ Gough, P Bouillet, A Strasser, M Leverkus, J Silke, H Walczak
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
Open access
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. S..
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Awarded by Seventh Framework Programme
Funding Acknowledgements
We thank Dr Geert van Loo (VIB Inflammation Research Center, Gent, Belgium) for providing K14Cre mice; Dr Vishva Dixit and Dr Kim Newton (Genentech, Inc., South San Francisco, CA) for providing Ripk3<SUP>KO</SUP> mice; Dr Razq Hakem (University of Toronto, Ontario) for Casp8<SUP>KO</SUP> mice; Helena Draberova, Paul Levy and his staff at the Kathleen Lonsdale Building (UCL, London, UK) for technical assistance; and Lorraine Lawrence (NHLI, Imperial College, London, UK) for histology service. This work was funded by a Wellcome Trust Senior Investigator Award (096831/Z/11/Z) and an ERC Advanced grant (294880) awarded to H.W. and NHMRC grants (project 602516, program 1113133) awarded to J.S. and H.W. or P.B. and A.S., respectively; N.P. is supported by the Swiss National Science Foundation (P300P3_158509), P.B., J.S. and A.S. are supported by NHMRC fellowships (1042629 1107149 and 1020363, respectively). This work is dedicated to the memory of our beloved colleague and friend Dr Martin Leverkus.