Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation
Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation
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DOI：
10.1038/sj.onc.1210042
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发表时间：
2007-04-12
期刊：
影响因子：
8
通讯作者：
Saya, H.
中科院分区：
文献类型：
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作者：
Kuninaka, S.;Iida, S-I;Saya, H.
丝氨酸蛋白酶Omi/HtrA2最初被认为是一种促凋亡分子，它能分解几种蛋白质来诱导细胞死亡。然而，最近的研究表明，Omi蛋白酶活性的丧失增加了对应激诱导的细胞死亡的敏感性。这些复杂的发现表明，OMI的蛋白酶活性不仅参与了细胞的凋亡，而且还参与了细胞的稳态。然而，OMI用来介导这一新过程的靶点尚不清楚。在此之前，我们已经证明了疣(WTS)/大肿瘤抑制因子1有丝分裂激酶与Omi的蛋白/盘状大蛋白/带状蛋白(PDZ)结构域相互作用，并促进其蛋白酶活性。我们现在报道WTS是Omi酶活性的底物，因此它不仅是该酶的调节因子，也是该酶的下游靶标。WTS需要与Omi PDZ结构域相互作用才能被蛋白降解。当caspase-9基因缺陷的小鼠胚胎。用星形孢子素处理成纤维细胞(MEF)，用激活的内源性Omi对WTS进行蛋白降解，而不诱导细胞死亡。因此，OMI的蛋白酶活性和WTS的蛋白降解不一定是细胞死亡所必需的。我们发现，尽管有丝分裂的持续时间没有显着变化，但HeLa细胞中OMi的缺失会导致细胞增殖加速。WTS的耗竭对S期的进展也有同样的影响。因此，OMI产生的WTS蛋白水解性片段(S)可能是G1/S进程的抑制因子。我们的数据揭示了Omi介导的WTS在间期对细胞周期进程的负调控中的作用，表明Omi除了凋亡之外还有另一种新的功能。
The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We nowreport that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic. broblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.