Second mitochondria-derived activator

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

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. 

In addition to cytochrome c, a second mitochondria-derived activator of caspases (SMAC) is also released from the mitochondrial intermembrane space. SMAC binds to an inhibitor of apoptosis protein (IAP) to prevent spontaneous caspase activation in a healthy cell. The IAP that binds to caspase-9 is called X-LAP. When SMAC binds to X-IAP, X-IAP is released from caspase-9. Autocleavage of the caspase-9 prodomain then exposes the catalytic site. Caspase-9 then activates caspase-3 which immediately cuts out the X-IAP binding domain from procaspase-9, preventing X-IAP inhibition and accelerating activation of both caspase-3 and caspase-9 (Fig. 13.11a), which digest all of the cell s proteins. The apoptotic cells also possess a caspase-activated DNase (CAD) that fragments chromosomal DNA. Other proteins from the mitochondrial intermembrane space can activate caspases by related mechanisms. The combination of mechanisms, or the overwhelming activation of any one of them, irreversibly propels a cell into apoptosis. 

Sun H, Nikolovska-Coleska Z, Lu J et al (2006) Design, synthesis, and evaluation of a potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase (Smac) mimetic. J Med Chem 49(26) 7916—7920... 

In addition to cytochrome c, other factors such as apoptosis inducing factor (AIF), endonuclease G, and second mitochondria-derived activator of caspases (Smac/DIABLO) may also be released from the inter-mitochondrial membrane space to exert their pro-apoptotic effects (see later). Recently, the endoplasmic reticulum (ER) has been identified as another organelle that can initiate the intrinsic apoptotic cascade in response to cellular stress. The ER is essential for proper... 

In addition to the release of cytochrome c, SMACs (second mitochondria-derived activator of caspases) are released due to the increase in mitochondrial manbrane permeability. These bind to lAPs (inhibitor of apoptosis proteins), preventing them from carrying out their normal function of caspase inhibition, allowing apoptosis to proceed. 

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