A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death |
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Authors: | Suzuki Y Imai Y Nakayama H Takahashi K Takio K Takahashi R |
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Institution: | Laboratory for Motor System Neurodegeneration, Brain Science Institute, Wako City, Saitama 351-0198, Japan. |
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Abstract: | X chromosome-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of caspase-3, -7, and -9. Smac/DIABLO, an inhibitor of XIAP, is released from mitochondria upon receiving apoptotic stimuli and binds to the BIR2 and BIR3 domains of XIAP, thereby inhibiting its caspase-inhibitory activity. Here we report that a serine protease called HtrA2/Omi is released from mitochondria and inhibits the function of XIAP by direct binding in a similar way to Smac. Moreover, when overexpressed extramitochondrially, HtrA2 induces atypical cell death, which is neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP. A catalytically inactive mutant of HtrA2, however, does not induce cell death. In short, HtrA2 is a Smac-like inhibitor of IAP activity with a serine protease-dependent cell death-inducing activity. |
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