The Serine Protease Omi/HtrA2 Regulates Apoptosis by Binding XIAP through a Reaper-like Motif

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

“…Several different Smac/DIA-BLO-deficient cells respond normally to various apoptotic stimuli, suggesting the existence of a redundant molecule or molecules compensating for a loss of Smac/DIABLO function (Okada et al 2002). However, overexpression of Omi/HtrA2 sensitizes cells to apoptosis, and its removal by RNA interference reduces cell death (Martins et al 2002). Meanwhile, our results showed that the administration of ucf-101 (Omi/HtrA2-specific protease inhibitor) could attenuate the decreased XIAP protein expression under normal conditions in aging rats.…”

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

“…the nucleus, lysosomes, the endoplasmic reticulum, or the cytosol) converge on mitochondria where they favor mitochondrial membrane permeabilization (MMP) [7][8][9]. Upon permeabilization of the mitochondrial outer membrane (OM), intermembrane space (IMS) proteins, that include caspase activators such as cytochrome c (Cyt c) [10], Omi/HtrA2 (Omi stress-regulated endoprotease/High temperature requirement protein A 2) [11,12] and Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with a low pI) [13,14], as well as caspase-independent death effectors like apoptosis-inducing factor (AIF) [15,16] and endonuclease G (EndoG) [17], are released into the cytosol. Cyt c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome (together with the apoptosis protease activating factor-1, i.e.…”

“…Cyt c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome (together with the apoptosis protease activating factor-1, i.e. APAF-1, and ATP/dATP) [18], while Omi/HtrA2 [11,12] and Smac/Diablo [13,14] favor the caspase cascade indirectly, by antagonizing the activity of endogenous inhibitors of caspases, i.e. the inhibitor of apoptosis proteins (IAPs).…”

“…Whereas AIF and Cyt c are considered the prototypic IMS proteins released upon MMP (due to microinjection experiments of recombinant molecules in intact cells, which demonstrated that either proteins suffice to induce the nuclear manifestations of apoptosis [61,62]), several other proteins are released from mitochondria upon OM permeabilization [63,64]. These include but are not limited to adenylate kinase [65], Smac/Diablo [63], Omi/HtrA2 [11,12], EndoG [17] as well as several pro-caspases [66].…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…The activation of caspase-9 subsequently cleaves and activates executioner caspases-3, -6 and/or -7, which successively cleave a multitude of cellular targets, such as poly (ADP-ribose) polymerase (PARP), inhibitor of caspase-activated DNAse and lamin, that initiates the dismantling of cellular components leading to cell demise (Degterev et al, 2003). Additionally, the concurrent release of second mitochondria-derived activator of caspase (Smac/DIABLO) and OMI/ HTRA2 during MOMP ensures optimal caspase activity is achieved by attenuating the XIAP (X-linked inhibitor of apoptosis protein), which inhibits caspases (Deveraux et al, 1997;Du et al, 2000;Verhagen et al, 2000;Martins et al, 2002).…”