Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

Abstract

Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis and promotes cytochrome c (Cyt c)dependent caspase activation by neutralizing inhibitor of apoptosis proteins (IAPs) via its IAP-binding motif. The protease activity of Omi/HtrA2 also contributes to the progression of both apoptosis and caspase-independent cell death. In this study, we found that wild-type Omi/HtrA2 is more effective at caspase activation than a catalytically inactive mutant of Omi/HtrA2 in response to apoptotic stimuli, such as UV irradiation or tumor necrosis factor. Although similar levels of Omi/HtrA2 expression, XIAP-binding activity, and Omi/HtrA2 mitochondrial release were observed among cells transfected with catalytically inactive and wild-type Omi/ HtrA2 protein, XIAP protein expression after UV irradiation was significantly reduced in cells transfected with wild-type Omi/HtrA2. Recombinant Omi/HtrA2 was observed to catalytically cleave IAPs and to inactivate XIAP in vitro, suggesting that the protease activity of Omi/HtrA2 might be responsible for its IAP-inhibiting activity. Extramitochondrial expression of Omi/HtrA2 indirectly induced permeabilization of the outer mitochondrial membrane and subsequent Cyt c-dependent caspase activation in HeLa cells. These results indicate that protease activity of Omi/HtrA2 promotes caspase activation through multiple pathways.

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

“…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. In 2004, Suzuki et al found that Omi/HtrA2 protease activity could reduce XIAP expression, and the release of HtrA2 from mitochondria might catalytically cleave and inactivate XIAP (Suzuki et al 2004). Taken together, these data indicated a nonredundant essential function of Omi/ HtrA2 in the induction of apoptosis though inactivation of XIAP in the aging heart.…”

Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

“…It has been thought that, similar to Smac/ DIABLO, HtrA2/Omi promotes apoptosis by inhibiting the apoptosis-suppressing activities of inhibitor of apoptosis proteins (IAPs) through a caspase-associated process [9]. However, there are also data suggesting that HtrA2/Omi might be able to induce apoptosis by means of its proteolytic activity without caspase activation [10,4]. Due to the scarcity of the existing data on the apoptotic function of AIF, EndoG and HtrA2/Omi in pathologic cardiac conditions, the precise regulatory mechanisms and the interdependence of these cellular factors in caspaseindependent pro-apoptotic signaling are largely unclear.…”

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

“…2 The mammalian HtrA2 protease, Omi, is much better known than other HtrA family members for its proapoptotic activity. 3 Most Omi resides in the intermembrane space of the mitochondria; however, endoplasmic reticulum (ER) and Golgi localization have also been reported. 4 Under apoptotic stimulation, a mature processed form of Omi is released into the cytosol where it binds to the cytosolic inhibitor of apoptosis proteins (IAPs) and inactivates their caspase-inhibitory activity 5 by direct cleavage.…”

“…4 Under apoptotic stimulation, a mature processed form of Omi is released into the cytosol where it binds to the cytosolic inhibitor of apoptosis proteins (IAPs) and inactivates their caspase-inhibitory activity 5 by direct cleavage. 3 Mature Omi that lacks the mitochondrial targeting sequence induces dramatic apoptosis-like morphological changes and cell death that is not blocked by caspase inhibitors. 6 Recently, increasing evidence has linked Omi to neurodegeneration and the cellular protein quality control system.…”