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

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

doi:10.1038/s41467-018-06155-8

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.

Highlights

The linear ubiquitin chain assembly complex (LUBAC), composed of HOIL-1-interacting protein (HOIP), Heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1) and Shank-associated RH domain-interacting protein (SHARPIN), is required for optimal tumour necrosis factor (TNF)-mediated gene activation and to prevent cell death induced by TNF
TNFR1 signalling can, result in cell death. This is triggered by a secondary cytoplasmic complex, called complex II, which is formed by the recruitment of Fas-associated protein with a death domain (FADD) and caspase-8 to receptorinteracting serine/threonine-protein kinase 1 (RIPK1)
We previously showed that LUBAC prevents complex II formation upon TNFR1 stimulation, thereby inhibiting TNFR1-mediated cell death[26,27,28]

Summary

Introduction

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. 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 for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone. TNFR1 signalling can, result in cell death This is triggered by a secondary cytoplasmic complex, called complex II, which is formed by the recruitment of Fas-associated protein with a death domain (FADD) and caspase-8 to receptorinteracting serine/threonine-protein kinase 1 (RIPK1). Whereas HOIP and HOIL-1 are both essential for LUBAC activity, SHARPIN only contributes to it

Objectives

Methods

Results

Conclusion