Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
J Biol Chem. 2012 Oct 5;287(41):34635-45. doi: 10.1074/jbc.M112.357509. Epub 2012 Aug 22.
Regulated intramembrane proteolysis is a widely conserved mechanism for controlling diverse biological processes. Considering that proteolysis is irreversible, it must be precisely regulated in a context-dependent manner. Here, we show that phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is cleaved in its N-terminal transmembrane domain in response to mitochondrial membrane potential (ΔΨ(m)) loss. This ΔΨ(m) loss-dependent cleavage of PGAM5 was mediated by presenilin-associated rhomboid-like (PARL). PARL is a mitochondrial resident rhomboid serine protease and has recently been reported to mediate the cleavage of PINK1, a mitochondrial Ser/Thr protein kinase, in healthy mitochondria with intact ΔΨ(m). Intriguingly, we found that PARL dissociated from PINK1 and reciprocally associated with PGAM5 in response to ΔΨ(m) loss. These results suggest that PARL mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria. Our data provide a prototypical example of stress-dependent regulation of PARL-mediated regulated intramembrane proteolysis.
调控的膜内蛋白水解是一种广泛存在的控制多种生物过程的机制。由于蛋白水解是不可逆的，它必须在依赖上下文的方式下被精确地调控。在这里，我们展示了磷酸甘油酸变位酶 5（PGAM5），一种线粒体丝氨酸/苏氨酸蛋白磷酸酶，在响应线粒体膜电位（ΔΨ(m)）损失时，其 N 端跨膜结构域被切割。这种 ΔΨ(m)损失依赖性的 PGAM5 切割是由早老素相关的类环指蛋白（PARL）介导的。PARL 是一种线粒体驻留的类环指丝氨酸蛋白酶，最近有报道称，在具有完整 ΔΨ(m)的健康线粒体中，PARL 介导了线粒体丝氨酸/苏氨酸蛋白激酶 PINK1 的切割。有趣的是，我们发现 PARL 与 PINK1 解离，并响应 ΔΨ(m)损失与 PGAM5 相互结合。这些结果表明，PARL 根据线粒体的健康状况介导 PINK1 和 PGAM5 的不同切割。我们的数据提供了一个依赖于应激的 PARL 介导的调控的膜内蛋白水解的典型范例。
