Smac DIABLO

Active caspases 8, 9 and 10 can convert caspase-3, the most abundant effector caspase from its pro-form to its active cleaved form. Cleavage of a number of different substrates by caspase-3 and also by caspase-6 and -7 which are two other executioner caspases besides caspase-3 then results in the typical morphology which is characteristic of apoptosis. Yet, the activation of caspase-3 and also of caspase-9 can be counteracted by IAPs, so called inhibitor of apoptosis proteins. However, concomitantly with cytochrome C also other proteins are released from mitochondria, including Smac/DIABLO. Smac/DIABLO and potentially other factors can interact with IAPs and thereby neutralize their caspase-inhibitory activity. This releases the breaks on the cell death program and allows apoptosis to ensue. 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

Besides cytochrome c and procaspase 9, other important apoptogenic factors are also released from the mitochondria, such as SMAC/DIABLO, Omi/HrtA2, AIF, and endonuclease G. The function of SMAC/DIABLO and Omi/HrtA2 is to activate caspase by suppressing the caspase inhibitory activity of IAP (Du et al., 2000 Verhagen et al., 2000). The protein... 

Smac/DIABLO Second mitochondrial activator of caspases/direct IAP-binding protein with low PI None... 

Keywords Neuron death Caspase lAP Smac/DIABLO TNF Fas PIDD RAIDD Neurodegenerative disease... 

Smac/DIABLO is not the only regulator of lAP activity. Several studies in mammalian cells have demonstrated the presence of additional molecules that suppress lAP activity in a similar fashion to Smac/DIABLO. The best-studied example is Omi/HtrA2 (Suzuki et al., 2001 Hegde et al., 2002 Martins et al., 2002 van Loo et al., 2002). This protein exhibits, as does Smac/DIABLO, mitochondrial localization with cytoplasmic release upon stimulation. 

It is worth mentioning that in death receptor-mediated apoptosis, cells can be divided into two groups depending on the requirement for mitochondria to induce a complete apoptotic response. Type I cells do not require the mitochondrial pathway because the recruitment of procaspase-8 into the DISC complex is enough to fully activate caspase-8 which then activates effector caspases. However, Type II cells are characterized by an incomplete apoptotic response unless mitochondria are involved (Scaffidi et al., 1999). In this type of cell, efficient activation of effector caspases requires the mitochondrial amplification loop (Fig. 5). Caspase-8 cleaves cytosolic Bid, a BH3-only protein, which when cleaved to tBid is able to translocate to the mitochondria and trigger release of the proapoptotic factors cytochrome c and Smac/DIABLO (Li et al., 1998 Deng et al., 2002). The release of cytochrome c triggers apoptosome formation, subsequent caspase-9 activation, and finally the activation of effector caspases such as caspase-3. 

Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406 855-862... 

Danial NN, Korsmeyer SJ (2004) CeU death critical control points. CeU 116 205-219 Denault JB, Eckelman BP, Shin H, Pop C, Salvesen GS (2007) Caspase-3 attenuates XIAP-mediated inhibition of caspase-9. Biochem J 405(1) 11-19 Deng Y, Lin Y, Wu X (2002) TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 16 33-45... 

Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Dost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP B1R3 domain. Nature 408 1004-1008... 

Guo E, Nimmanapalli R, Paranawithana S, Wittman S, Griffin D, Bali P, O Bryan E, Eumero C, Wang HG, Bhalla K. Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAlL-induced apoptosis. Blood 2002 99 3419-3426. 

Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and clAPl in situ. J. Biol. Chem. 2002 277 44236-44243. 

Smac/Diablo a mitochondrial protein that promotes some forms of apoptosis by neutralizing one or more members of the lAP family of apoptosis inhibitory proteins. 

---