The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity.
The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity.
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DOI：
10.1016/j.bbrc.2009.07.079
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发表时间：
2009-09
影响因子：
3.1
通讯作者：
Hye-Min Park;Goo-Young Kim;Min-Kyung Nam;Geun-Hye Seong;Chul Han;K. Chung;Seongman Kang;H. Rhim
中科院分区：
文献类型：
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作者：
Hye-Min Park;Goo-Young Kim;Min-Kyung Nam;Geun-Hye Seong;Chul Han;K. Chung;Seongman Kang;H. Rhim
丝氨酸蛋白酶 HtrA2 不仅对调节细胞凋亡而且对细胞稳态也很重要。最近，多项证据表明 HtrA2 可能与 Parkin 密切相关。然而，人们对 HtrA2 和 Parkin 之间的功能关系知之甚少。在这里，我们发现 HtrA2 通过在细胞应激时从线粒体释放 HtrA2 与 Parkin 共定位于细胞质中。此外，在相同应激条件下，与HtrA2敲除（HtrA2−/−）MEF中的相比，野生型（HtrA2+/+）小鼠胚胎成纤维细胞（MEF）中Parkin的内源水平显着降低。通过切割和结合测定，我们证明 HtrA2 特异性结合并直接切割 E3 泛素 (Ub) 连接酶 Parkin。有趣的是，HtrA2 介导的 Parkin 裂解不可逆地破坏 Parkin 介导的 synphilin-1 泛素化和自泛素化，表明 HtrA2 可能在泛素蛋白酶体系统涉及的 Parkin 相关途径中发挥关键作用。
The serine protease HtrA2 is important in regulating not only apoptosis but also cellular homeostasis. Recently, several lines of evidence suggest that HtrA2 may be intimately associated with Parkin; however, little is known about the functional relationships between HtrA2 and Parkin. Here we have shown that HtrA2 is co-localized with Parkin in the cytosol through the release of HtrA2 from the mitochondria upon cellular stresses. Moreover, endogenous levels of Parkin were significantly decreased in wild-type (HtrA2+/+) mouse embryonic fibroblasts (MEF) compared with those in HtrA2-knockout (HtrA2−/−) MEF under the same stress conditions. Using cleavage and binding assays, we have demonstrated that HtrA2 specifically binds to and directly cleaves the E3 ubiquitin (Ub) ligase Parkin. Interestingly, the HtrA2-mediated Parkin cleavage irreversibly disrupts Parkin-mediated synphilin-1 ubiquitination and autoubiquitination, indicating that HtrA2 may play a critical role in the Parkin-related pathway involved in the ubiquitin proteasome system.