Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways.
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.
Suzuki
Y
Y
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama, Japan.
Takahashi-Niki
K
K
Akagi
T
T
Hashikawa
T
T
Takahashi
R
R
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002384:Catalysis; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D045304:Cytochromes c / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein
D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; D024101:Mitochondrial Proteins; D011506:Proteins; C047610:SC5b-9 protein complex; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003165:Complement System Proteins; D045304:Cytochromes c; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases