Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice
Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice
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DOI：
10.1128/mcb.24.22.9848-9862.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Downward, J
中科院分区：
文献类型：
--
作者：
Martins, LM;Morrison, A;Downward, J
丝氨酸蛋白酶HtrA2/Omi在细胞凋亡刺激下从线粒体膜间隙释放。一旦进入胞浆，HtrA2/Omi通过其氨基末端的Reaper相关基序与凋亡抑制蛋白(IAPs)结合，从而诱导caspase活性，从而促进细胞死亡，并通过自身的蛋白酶活性介导caspase非依赖性死亡。我们在这里报告了由于HtrA2/Omi基因Prss 25的定向缺失而完全缺乏HtrA2/Omi表达的小鼠的表型。这些动物或从它们衍生的细胞没有显示出细胞死亡率降低的证据，但相反，纹状体中的神经元数量减少，导致具有帕金森表型的神经退行性疾病，导致小鼠出生后30天左右死亡。这些小鼠的表型表明，关键是这种蛋白的蛋白酶功能，而不是它的IAP结合基序。另一个主要的LAP结合蛋白Smac/Diablo的同时缺失并没有明显改变HtrA2/Omi基因敲除小鼠或从它们衍生的细胞的表型，这一发现强化了这一结论。因此，哺乳动物HtrA2/Omi在体内的功能可能与其细菌同源物degs和DegP相似，后者参与细胞应激保护，而不像果蝇中促凋亡的Reaper家族蛋白。
The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. 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. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. 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. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major LAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. 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.