Figure 2

Model of TNFR1 signaling with and without LUBAC activity. Binding of trimeric TNF crosslinks the extracellular domains of three TNFR1 molecules and induces the formation of the TNF-RSC (also referred to as complex I). The tripartite LUBAC (ochre) is recruited to the TNF-RSC in a TRADD-, TRAF2- and cIAP-dependent manner (left panel) [16, 19]. LUBAC activity in the TNF-RSC results in linear ubiquitination of RIP1 and NEMO [19] and enables the NF-κB and MAPK pathways to be activated to their full physiological extent. After a delay, and probably as a consequence of deubiquitination events at the membrane-bound TNF-RSC, the composition of the complex changes, and a second complex, complex II, appears in the cytosol [45]. Complex II (not shown) recruits FADD and caspase- 8, which are responsible for the induction of apoptosis, and includes RIP1 and RIP3, which mediate necroptosis. In the presence of LUBAC, however, the induction of cell death is prevented, probably by both stabilization of complex I by linear ubiquitination and the actions of genes induced by the NF-κB and MAPK pathways [16]. In the absence of SHARPIN (right panel), the other two LUBAC components are also drastically diminished, TNF-induced gene activation is attenuated and the TNF-RSC is destabilised, resulting in enhanced complex II formation and, consequently, cell death induction by apoptosis and necroptosis. Note that we have drawn the ubiquitin chains as diubiquitins. The actual length of the individual ubiquitin chains attached to components of the TNF-RSC - or indeed to components of any other signaling complex - is currently unknown.