Abstract
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.
Highlights
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo
Since K63- and K48-linked ubiquitination regulates TRAIL-induced cell-death signalling and linear ubiquitination controls multiple immune signalling pathways, we examined whether LUBAC may be implicated in TRAIL signalling
Given that TRAIL can induce both apoptosis and necroptosis, we investigated the modality of TRAIL-induced death in HOIP-deficient (HOIP KO) Mouse embryonic fibroblasts (MEFs)
Summary
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo. 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, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. By limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC restricts TRAIL-induced necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC promotes TRAILinduced activation of NF-jB and, the production of cytokines, downstream of FADD, caspase-8 and cIAP1/2. LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
