TNF receptor‐1 (TNFR1) and TRAIL death receptors preferentially induce pro‐inflammatory or cytotoxic signaling, respectively, via distinct plasma membrane and cytosolic complexes. New studies identifying the pro‐inflammatory factors TRAF2, RIP, and LUBAC in TRAIL death receptor complexes suggest that the latter are more “TNFR1‐like” than anticipated and argue for revision of prevailing models of spatio‐hierarchical TRAIL‐induced signaling complex assembly.
See also: E Lafont et al
Tumor necrosis factor (TNF) receptor‐1 (TNFR1) and the TNF‐related apoptosis‐inducing ligand (TRAIL) receptors TRAILR1 and TRAILR2 share the characteristic “death domain” (DD) and make use of basically the same set of signaling proteins to induce apoptotic or necroptotic cell death, but also to engage pro‐inflammatory signaling pathways such as the classical NF‐κB pathway. Interestingly, however, while pro‐inflammatory signaling is dominant in the case of TNFR1, cytotoxic activities are most prominent in TRAIL death receptor signaling. These relative preferences appeared to be due to differences in the localization and hierarchy of assembly of signaling complexes triggering cell death and activation of the pro‐inflammatory IκB kinase (IKK) complex (for review see Siegmund et al, 2016). TNFR1 stimulation triggers assembly of a membrane‐localized complex devoid of cytotoxic activities. This “complex I” contains the DD adapter protein TRADD and the serine/threonine kinase RIP, which recruit complexes of TRAF2 and the E3 ubiquitin ligases cIAP1 or cIAP2, as well as the linear ubiquitin chain assembly complex (LUBAC). RIP modification by these E3 ligases with K63‐linked and M1‐linked (linear) ubiquitin chains creates docking sites for the ubiquitin‐binding domain‐containing subunits of the IKK complex and its activator, the TAB 2‐TAK1 complex, and this way ensures robust …
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