Journal of Molecular Cell Biology Advance Access published online on October 16, 2009
Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjp034
Type I and Type II Pathways of Fas-mediated Apoptosis Are Differentially Controlled by XIAP
The Campbell Family Cancer Research Institute, University Health Network, Toronto, ON, Canada
* Correspondence to: Zhenyue Hao, E-mail: zyhao{at}uhnres.utoronto.ca; Tak W. Mak, E-mail: tmak{at}uhnres.utoronto.ca
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The mechanism by which Fas activates the apoptotic pathway differs in so-called type I and type II cells. X chromosome-linked inhibitor of apoptosis protein has now been revealed as an important molecule that is differentially regulated in type I vs. type II cells.
Fas (CD95) is a death domain containing receptor that activates the extrinsic apoptotic pathway. Upon engagement by its ligand or agonistic antibody, the adaptor molecule Fas-associated death domain protein is recruited to the receptor and a death-inducing signaling complex (DISC) is formed. The DISC activates the initiator protease caspase-8, which triggers activation of the effector proteases caspase-3 and -7 that drive the cellular changes characteristic of apoptosis. In contrast, the intrinsic apoptotic pathway is initiated in response to cellular stress and depends on the activation of pro-apoptotic Bcl-2 family members such as BH3 interacting domain death agonist (Bid) and Bax/Bak. Ultimately, cytochrome c is released from the intermembrane space of the mitochondrion into the cytosol, where it binds to Apaf-1 to form the apoptosome. The apoptosome recruits and activates caspase-9, which in turn activates caspase-3 and -7. Also released from the mitochondrion in response to cellular stress is second mitochondria-derived activator of caspase (SMAC), which interferes with the ability of X chromosome-linked inhibitor of apoptosis protein (XIAP) and other IAPs to block the activation of caspase-3, -7 and -9. Thus, in general, XIAP inhibition has been thought to facilitate apoptosis.
Fas-expressing tissues and cells are classified as either type I or type II based mainly on whether the intrinsic apoptotic pathway contributes to the amplification of the caspase cascade (Figure 1). Although both type I and type II cells are equally sensitive to Fas-mediated apoptosis, the signaling pathways leading to this cell death are distinct. In type I cells, caspase-8 is activated by the DISC, and activated caspase-8 triggers the activation of caspase-3 and -7 without the involvement of the intrinsic pathway. In type II cells, caspase-8 activated by the DISC cleaves and thus activates the pro-apoptotic Bcl-2 family member Bid. The truncated Bid protein (tBid) then triggers the mitochondrion to release cytochrome c through activation of Bax/Bak. This released cytochrome c then initiates apoptosome formation and effector caspase activation as described above.
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, activation;—|, inhibition.The type II pathway of Fas-mediated apoptosis is critical for amplifying signaling during Fas-induced hepatocyte death. Studies of Bid knockout (KO) mice, Bax/Bak double KO mice and Bcl-2 transgenic mice have shown that all of these mutants are resistant to Fas-induced fatal hepatitis (Yin et al., 1999; Wei et al., 2001; Kaufman et al., 2007). Surprisingly, genetic ablation of the cytochrome c-mediated apoptotic function in cytochrome c knock-in mice fails to render these animals resistant to Fas-induced fatal hepatitis (Hao et al., 2005, unpublished observation). In addition, SMAC-deficient mice, in which the IAPs cannot be counteracted by SMAC, are sensitive to Fas-induced fatal hepatitis (Okada et al., 2002). Thus, it has been controversial whether mitochondrial downstream effectors are truly involved in type II Fas signaling.
A recent elegant study published in Nature by Jost et al. demonstrates that the regulation of XIAP dictates whether a cell will exercise type I or type II Fas-induced apoptosis (Jost et al., 2009). Although basal levels of XIAP are similar in type I (thymocytes) and type II (hepatocytes) cells, Fas stimulation leads to a rapid reduction in XIAP levels in thymocytes but an increase in XIAP concentration in hepatocytes. Xiap deletion does not affect the Fas-induced death of thymocytes but sensitizes hepatocytes to Fas-mediated apoptosis. Intriguingly, activated caspase-3 is required for both the XIAP reduction in type I cells and the XIAP increase in type II cells. Strikingly, genetic ablation of Xiap in Bid KO mice reverses their resistance to Fas-induced lethality, such that death occurs with only a slight delay in kinetics compared with wild-type mice.
At the molecular level, engagement of Fas in Xiap/Bid double KO hepatocytes leads to activation of caspase-8, -9, -3 and -7. This activation stands in contrast to the lack of efficient activation seen in Bid KO hepatocytes. Thus, genetic deletion of Xiap in hepatocytes changes the Fas apoptosis phenotype of these cells from type II to type I, most likely due to the removal of XIAP's inhibition of caspase-8-mediated activation of caspase-3 and -7. These results also suggest that the activation of caspases in hepatocytes is normally blocked by XIAP, and that the ratio of SMAC:XIAP concentrations within a cell may determine its preferred pathway of Fas-induced apoptosis. In the light of the present study, it is tempting to speculate that activation of caspase-9 through the apoptosome and inhibition of XIAP through SMAC are both required for Fas-induced apoptosis in hepatocytes. Inhibition of both pathways via genetic manipulation in mice may allow the elucidation of whether and how the apoptosome and SMAC are involved in Fas-induced apoptosis of hepatocytes.
It remains unclear what mechanism causes the dramatic differential regulation of XIAP levels in response to Fas engagement in type I and II cells. Interestingly, like the genetic ablation of Xiap in Bid KO mice, the application of an SMAC mimetic in Bid KO mice reverses the resistance of hepatocytes in these animals to Fas-induced destruction. These results suggest that the caspases, SMAC and XIAP form an axis that plays an essential role in the Fas-induced apoptosis of hepatocytes, and that the relative concentrations of these molecules tip the balance between type I and type II Fas signaling. Given the therapeutic potential of SMAC mimetics in sensitizing tumor cells to TNF-induced apoptosis (Wu et al., 2007), elucidation of the molecular mechanisms underlying these observations will be essential for the development of safe and effective drugs.
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