![]() ![]() DegS detects unfolded outer membrane porins in the periplasm, triggering a signaling protease cascade leading to adaptive changes in gene expression ( 36). DegP is a protein that protects against heat stress and that acts as a chaperone for unfolded proteins at low temperatures, while acting to degrade them at elevated temperatures ( 25). Well-characterized members of the family include DegS and DegP in E. While Smac/DIABLO has no obvious catalytic function and no clear homologues (outside of the 4-amino-acid Reaper motif) in invertebrates, HtrA2/Omi is a member of a well-conserved family of PDZ domain-containing serine proteases that are found in most eukaryotes and prokaryotes. Alternatively, the high degree of redundancy among IAPs, and possibly also among Reaper motif-containing proteins, may make their in vivo function hard to analyze by single-gene deletion experiments. It is possible that IAPs and their antagonists play relatively minor roles in the regulation of apoptosis in mammals, unlike in flies. Similarly, mice with a deletion of the gene for the broadly expressed IAP family member XIAP show no abnormal phenotype ( 6). Cells derived from these Smac/DIABLO knockout mice also display normal apoptosis regulation. However, there is relatively little evidence that endogenous Smac/DIABLO plays an important physiological role in the regulation of apoptosis ( 33) and mice with the gene for this protein deleted show no detectable abnormalities ( 19). When overexpressed, Smac/DIABLO can sensitize cells to apoptotic stimuli. ![]() Smac/DIABLO is another mammalian mitochondrial protein containing an amino-terminal Reaper motif that has been identified due to its ability to interact with and antagonize IAPs ( 2, 34). In addition, HtrA2/Omi has also been implicated in mediating caspase-independent cell death through its own serine protease activity ( 8, 27). HtrA2/Omi has therefore been proposed to be a proapoptotic protein analogous to Reaper that removes the protective effect of IAPs and thus potentiates the ability of the cytochrome c that is released from the mitochondria at the same time to trigger caspase activation ( 16, 29, 30, 38). ![]() This binding results in the increase of the proteolytic activity of HtrA2/Omi ( 18) and has also been reported to cause proteolytic degradation of bound IAPs ( 26, 40). Binding of HtrA2/Omi to IAPs relieves their inhibitory activities towards caspases. Following apoptotic stimuli, HtrA2/Omi is released from the mitochondria into the cytosol, where it uses this motif to bind to inhibitor of apoptosis proteins (IAPs) ( 8, 17, 27, 35). A proteolytic-processing event reveals an amino-terminal sequence motif related to that of the critical Drosophila melanogaster proapoptotic proteins Reaper, Grim, and Hid. HtrA2/Omi is localized to the mitochondrial intermembrane space by a mitochondrion-targeting sequence. Like the bacterial protein, HtrA2/Omi has a PDZ domain in addition to the serine protease domain. The serine protease HtrA2/Omi was identified as a mammalian homologue of the Escherichia coli protein HtrA, also known as DegP ( 3, 5). Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster. ![]() This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. ![]()
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