LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L Academic Article uri icon

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.

authors

  • Taraborrelli, L
  • Peltzer, N
  • Montinaro, A
  • Kupka, S
  • Rieser, E
  • Hartwig, T
  • Sarr, A
  • Darding, M
  • Draber, P
  • Haas, TL
  • Akarca, A
  • Marafioti, T
  • Pasparakis, M
  • Bertin, J
  • Gough, PJ
  • Bouillet, P
  • Strasser, A
  • Leverkus, M
  • Silke, John
  • Walczak, H

publication date

  • 2018