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. 2022 Oct 4;30(2):237–249. doi: 10.1038/s41418-022-01059-z

Fig. 2. Non-canonical TRAIL signaling.

Fig. 2

In complex I and complex II downstream of FADD, caspase-8, TRAF2 and cIAP1/2, the linear ubiquitin chain-assembly complex (LUBAC) limits caspase-8 activation and enables the recruitment of the IKK complex to both complexes promoting gene activation and cytokine production. When caspases are inhibited RIPK1 can induce NF-κB [146]. FADD is essential for the formation of both complex I and complex II it is therefore also required for TRAIL-induced gene-activatory signaling [78, 147]. Caspase-8 presence, but not its activity is crucial for TRAIL-mediated gene activation [147, 148]. Besides NF-ĸB, TRAIL is also implicated in the activation of mitogen activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), p38 and extracellular regulated kinase (ERK)1/2, which control central physiological processes such as gene expression, cell proliferation and inflammation [149, 150]. Additionally, independently of FADD the membrane-proximal domain (MPD) of TRAIL-R2 can activate Rac1 and promote progression, invasion and metastasis [39].