Figure 7.
Model of TRAIL-activated proapoptotic and antiapoptotic pathways. TRAIL stimulates its receptors, TRAIL-R1 and/or TRAIL-R2, resulting in recruitment of the adapter protein FADD and activation of procaspase-8 within the DISC. Caspase-8 subsequently processes procaspase-3, but active caspase-3 is rapidly inhibited by IAPs, including XIAP. Caspase-8 also cleaves and activates BID, and tBID would normally induce BAK-dependent MOMP and release the IAP antagonist Smac/DIABLO. However, TRAIL receptor stimulation simultaneously activates an antiapoptotic TAK1→MKK3/MKK6→p38 MAPK signaling pathway that transcriptionally upregulates MCL-1, which in turn sequesters/neutralizes tBID. Disruption of this signaling pathway at any step sensitizes cells to TRAIL, but remarkably, even after mitochondrial injury, mitochondrial-generated ROS activate a secondary JNK pathway that similarly leads to transcriptional upregulation of MCL-1 and partial protection from cell death. As shown in the inset, ROS are most likely produced as a result of inefficient electron transfer, after the release of cytochrome c, or perhaps in response to caspase-dependent cleavage of complex I proteins including NDUFS144