Abstract
The current study demonstrates a novel cross-talk mechanism between the TRAIL receptor death signaling pathway and the mitochondria. This newly identified pathway is regulated at the mitochondrial outer membrane by a complex between the prosurvival Bcl-2 member, Mcl-1 and the BH3-only protein, Bim. Under non-apoptotic conditions, Bim is sequestered by Mcl-1. Direct degradation of Mcl-1 by TRAIL-activated caspase-8 or caspase-3 produces Mcl-1-free Bim that mediates a Bax-dependent apoptotic cascade. Using Mcl-1 or Bim RNAi, we demonstrate that a loss in Mcl-1 expression significantly enhances the mitochondrial apoptotic response to TRAIL that is now mediated by freed Bim. Whereas overexpression of Mcl-1 contributes to the preservation of the mitochondrial membrane potential, Mcl-1 knockdown facilitates the Bim-mediated dissipation of this potential. Loss of Mcl-1 contributes to an increased level of caspase activity downstream of the mitochondrial response to TRAIL. Furthermore, the Mcl-1 expression level at the mitochondrial outer membrane determines the release efficiency for the apoptogenic proteins cytochrome c, Smac, and HtrA2 in response to Bim. These are the first findings to demonstrate the involvement of Bim in the TRAIL-mediated mitochondrial cascade. They also suggest that Mcl-1 may serve as a direct substrate for TRAIL-activated caspases implying the existence of a novel TRAIL/caspase-8/Mcl-1/Bim communication mechanism between the extrinsic and the intrinsic apoptotic pathways.
Highlights
Fragment of Bid translocates to the mitochondria where it activates Bax and thereby induces the release of the apoptogenic proteins, cytochrome c, AIF, endonuclease G, Smac, and HtrA2 [7, 8]
We investigated the possibility that the mitochondrial Mcl-11⁄7Bim complex serves as an additional link between the extrinsic and the intrinsic apoptotic pathways activated by TRAIL
We demonstrate that Mcl-1 serves to maintain the mitochondrial membrane potential that is disrupted by the presence of Mcl-1-free Bim, leading to the release of apoptogenic proteins
Summary
Fragment of Bid translocates to the mitochondria where it activates Bax and thereby induces the release of the apoptogenic proteins, cytochrome c, AIF, endonuclease G, Smac, and HtrA2 [7, 8]. Involvement of Caspase-8 and Caspase-3 Activity in the Down-regulation of Mcl-1 during TRAIL-mediated Apoptosis—To investigate a potential role for Mcl-1 in the mitochondrial response to TRAIL, we assessed its expression in lysates of tumor cell lines treated with TRAIL.
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