Finding of a new cell death inducer Motor System Neurodegeneration Research Team Apoptosis is a phenomenon whereby cells actively bring about their own demise, and is frequently referred to as "cellular suicide". Although apoptosis is "death", it is a mechanism that is indispensable to birth, development, and maintenance of life in organisms. For example, apoptosis is needed when more cells are generated than are required in formation of the human body. In adults, as well, impediments to apoptosis can cause cancer and autoimmune disorders. Conversely, excessive apoptosis apparently leads to neurodegenerative disorders such as Alzheimer's disease. The apoptosis mechanism is operative in insects such as flies, as well as in human beings. The enzyme caspase plays a major role. Caspase acts by slicing through various important proteins inside of cells, much the way scissors cut paper. It is known as "the killer", but there also known to be proteins that halt this killer's actions. The apoptosis-blocking protein IAP is one of these. IAP forcefully suppresses caspase's enzymatic activity. We found that IAP suppresses apoptosis by decomposing and scattering caspase, rather than merely deactivating it.1 Thus, apoptosis in organisms seems to be proficiently regulated by killer caspase, and by IAP, which acts as a bodyguard to suppress the killer. However, surprisingly enough, proteins have been found that, in turn, block the action of IAP. The protein known as Smac or DIABLO ordinarily remains hidden inside mitochondria, but when a stimulus that triggers apoptosis is applied to a cell, it emerges forcefully from the mitochondria, and bonds onto IAP, which is normally present in the cytoplasm. IAP to which Smac has bonded is rendered incapable of suppressing caspase, so that apoptosis can proceed. In the present study, we found a mitochondrial protein, Omi/HtrA2, that has an action similar to that of Smac.2 HtrA2 is released from mitochondria into the cytoplasm in response to apoptotic stimuli (Figure 1). HtrA2 released into the cytoplasm bonds securely onto IAP, similarly to Smac. As a result, it enhances caspase activity, thus promoting apoptosis. However, we found that HtrA2 has an enzymatic action that Smac lacks, whereby it severs proteins that have properties different from those of caspase. We noted that when HtrA2 that has been rendered incapable of bonding onto IAP is introduced into cells, its enzymatic activity causes cells to become globular, and contract, after which they slowly die (Figure 2). This HtrA2 activity cannot be stopped by deactivating caspase. Hence, we found that HtrA2 is a completely new kind of cell death inducer, with a double action whereby it both enhances the action of caspase by impeding that of IAP, thus promoting apoptosis, and at the same time brings about cell death through an enzymatic activity of its own, regardless of caspase. We found that when the expression level of HtrA2 is reduced by means of special methods, cell death occurred less readily, indicating that it plays an important physiological role. In other results that we have obtained recently, we found that the release of HtrA2 from mitochondria coincides with the timing with which symptoms of some kinds of neurodegenerative disorders proceed, and this aroused our interest as to its relationship to these diseases. We are making efforts at present to identify factors that regulate HtrA2. We hope that this research will provide the basis for development of new therapies for neurodegenerative diseases. 1. Suzuki, Y., Nakabayashi, Y., and Takahashi, R.: Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its antiapoptotic effect in Fas-induced cell death. Proc. Natl. Acad. Sci. U.S.A. 98: 8662-8667 (2001) 2. Suzuki, Y., Imai, Y. Nakayama, H., Takahashi, K Takio, K., and Takahashi, R.: A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8: 613-21 (2001) 　 Fig. 1 Here it can be seen that when cell death is induced under ultraviolet (UV) radiation, HtrA2 is released from the mitochondria (which have a reticulated appearance) into the cytoplasm. Known mitochondrial cell death inducer cytochrome-c exhibits exactly the same behavior. 　 Fig. 2 When HtrA2 is made to express through gene transfer, the cells become globular, shrink, and die. In this case, caspase activity is not increased, and cell death cannot be suppressed by caspase inhibition.