Diablo homolog, mitochondrial is a protein in humans that is encoded by DIABLO gene. Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/bruce by inhibiting its binding to caspases. Isoform 3 attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Isoform 3 also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Isoform 1 is defective in the capacity to down-regulate the XIAP/BIRC4 abundance.
Direct inhibitor of apoptosis-binding protein with a low isoelectric point, pI (DIABLO), also known as a second mitochondria-derived activator of caspase (SMAC), is a pro-apoptotic mitochondrial protein. DIABLO/SMAC is normally localized within the mitochondria. It has an N-terminus with a stretch of amino acids characteristic of mitochondrial targeting sequences that are removed from proteins upon import into mitochondria. Following an apoptotic trigger, mitochondria undergo loss of inner mitochondrial membrane potential and subsequent mitochondrial membrane permeabilization (MMP). The N-terminally processed DIABLO/SMAC is released into the cytosol together with cytochrome c. Cytochrome c directly activates the Apaf-1/caspase-9 apoptosome and downstream effector caspases, leading to apoptosis. However, the activity of mature caspases is inhibited by their interaction with the inhibitor of apoptosis proteins (IAPs). DIABLO/SMAC promotes apoptosis by abrogating the inhibitory effect of IAPs through physical interactions. Amino-terminal sequences in DIABLO/SMAC are required for its interaction with IAPs. Studies demonstrated that DIABLO/SMAC interacts with the BIR2 and BIR3 domains of XIAP, allowing the release of caspase-3 and caspase 9, respectively. Several studies have shown that overexpression of DIABLO/SMAC sensitizes tumor cells to apoptosis. The role of DIABLO/SMAC, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. Furthermore, amino-terminal DIABLO/SMAC derivatives and small molecules that mimic the DIABLO/SMAC function could be a potential therapy for tumors with the expression of IAPs.