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

Tobias Longin Haas, Lucia Taraborrelli, Nieves Peltzer, Antonella Montinaro, Sebastian Kupka, Eva Rieser, Torsten Hartwig, Aida Sarr, Maurice Darding, Peter Draber, Ayse Akarca, Teresa Marafioti, Manolis Pasparakis, John Bertin, Peter J. Gough, Philippe Bouillet, Andreas Strasser, Martin Leverkus, John Silke, Henning Walczak

Risultato della ricerca: Contributo in rivistaArticolo in rivista

35 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)3910-3920
Numero di pagine11
RivistaNature Communications
Volume9
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Biochemistry, Genetics and Molecular Biology (all)
  • Chemistry (all)
  • Physics and Astronomy (all)

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