title: The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.
abstract: The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkagesde novoLUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptosis. We identify RIPK1 and caspase-8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL-induced RIPK1-independent apoptosis, HOIP presence, but not its activity, is required for preventing necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC also promotes TRAIL-induced activation of NF-κB and, consequently, the production of cytokines, downstream of FADD, caspase-8 and cIAP1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation.
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lafont
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Chahrazade
authors.initials: C
authors.lastname: Kantari-Mimoun
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: De Miguel
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hartwig
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kupka
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Spit
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGMBH), Heidelberg, Germany.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.identifier: 0000-0002-6312-4591
authors.initials: H
authors.lastname: Walczak
mesh_terms: D016923:Cell Death; D002460:Cell Line; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: 
  LUBAC
  ; 
  TRAIL
  ; NF‐κB; cell death; ubiquitin