The linear ubiquitin chain assembly complex regulates TRAIL‐induced gene activation and cell death

• Elodie Lafont ^[1] ; Chahrazade Kantari‐Mimoun ^[1] ; Peter Draber ^[1] ; Diego De Miguel ^[1] ; Torsten Hartwig ^[1] ; Matthias Reichert ^[1] ; Sebastian Kupka ^[1] ; Yutaka Shimizu ^[1] ; Lucia Taraborrelli ^[1] ; Maureen Spit ^[1] ; Martin R Sprick ^[2] ; Henning Walczak ^[1]
  1. [1] University College London

     University College London

     Reino Unido

     
  2. [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine

     Heidelberg Institute for Stem Cell Technology and Experimental Medicine

     Stadtkreis Heidelberg, Alemania

     
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 9, 2017, págs. 1147-1166
• Idioma: inglés
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• Resumen

  • The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo. LUBAC 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.