TRAIL canonical signalling pro-apoptotic pathway

Schematic representation of TRAIL canonical signalling pro-apoptotic pathway. Illustration of the membrane-bound TRAIL, expressed by cytolytic immune cells such as NK cells inducing apoptosis in cancer cells. TRAIL binding to DR4 and/or DR5 agonist receptors, induce their aggregation and the recruitment of FADD and caspase-8/10 forming the DISC (death-inducing signalling complex), or complex I, which ultimately will lead to the activation of the effector caspases 3/6/7. Their activation by enzymatic cleavage is either triggered directly by the active caspase-8 or indirectly through caspase-8-mediated Bid cleavage. Bid cleavage allows Bax translocation to mitochondria and the release of cytochrome c, whose binding with Apaf-1, amplifies apoptosis-induced by TRAIL receptors (extrinsic pathway), through the formation of a soluble pro-apoptotic complex coined apoptosome, that allows activation of the initiator caspase-9. The active caspase-9 will in turn amplify the signal by cleaving and activating the effector caspases 3/6/7. The main inhibitors of this signalling pathway are represented in red, including the antagonist receptors (DcR1/2/3 and OPG) which compete for TRAIL binding or c-FLIP and XIAP the main caspase-8 and effector caspases inhibitor inhibitors, respectively. In addition, a schematic representation of the non-canonical signalling associated with complex I is shown, mainly describing potential activation of NF-κΒ pathway, which besides protecting the cells from TRAIL-induced apoptosis is involved in promoting TRAIL’s pro-tumoral activity. Main TRAIL-induced apoptosis inhibitors are shown in red

Publication

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling (2024) Abderrahmane Guerrache, et al. Cells. 2024 Mar;13(6). Figure: F3. Homo sapiens

Disease mentions