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 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 RIPK 1/ RIPK 3/ MLKL ‐containing complex, LUBAC also restricts TRAIL ‐induced necroptosis. We identify RIPK 1 and caspase‐8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL ‐induced RIPK 1‐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 cIAP 1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and  II , two platforms which both trigger cell death and gene activation. image The linear ubiquitin chain assembly complex ( LUBAC ), known to play key role in various immune receptor pathways, is identified as a crucial regulator of TRAIL ‐induced signalling complexes, restricting apoptosis and necroptosis while promoting cytokine production. TRAIL ‐induced complex I and II both act as death‐inducing and gene‐activatory signalling platforms. LUBAC is recruited to TRAIL complex I downstream of FADD , caspase‐8 and cIAP 1/2, yet independently of RIPK 1. LUBAC is recruited to complex I and II in TRAIL signalling and restricts TRAIL ‐induced necroptosis and apoptosis. LUBAC promotes gene expression and cytokine production by recruiting the IKK complex to TRAIL complexes I and II .