Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, Heidelberg, Germany.
J Neurochem. 2011 Jun;117(5):856-67. doi: 10.1111/j.1471-4159.2011.07253.x. Epub 2011 Apr 13.
Intramembrane proteolysis is a conserved mechanism that regulates a variety of cellular processes ranging from transcription control to signaling. In mitochondria, the inner membrane rhomboid protease PARL has been implicated in the control of life span and apoptosis by a so far uncharacterized mechanism. Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. As targeting of this precursor to the outer mitochondrial membrane has been shown to trigger mitophagy, we suggest that the PARL-catalyzed removal of the Pink1 signal sequence in the canonical import pathway acts as a cellular checkpoint for mitochondrial integrity. Furthermore, we show that two Parkinson's disease-causing mutations decrease the processing of Pink1 by PARL, with attendant implications for pathogenesis.
膜内蛋白水解是一种保守的机制，它调节从转录控制到信号转导等各种细胞过程。在线粒体中，内膜菱形蛋白酶 PARL 通过一种迄今尚未确定的机制参与控制寿命和细胞凋亡。在这里，我们表明 PARL 在内膜锚定区域切割与人帕金森病相关的 Pink1。成熟的 Pink1 随后可以自由释放到细胞质或线粒体膜间隙中。当线粒体膜电位去极化时，Pink1 和 PARL 催化加工的经典导入被阻断，导致 Pink1 前体的积累。由于已经表明将这种前体靶向到外线粒体膜会触发线粒体自噬，因此我们认为 Pink1 信号序列在经典导入途径中的 PARL 催化去除是线粒体完整性的细胞检查点。此外，我们表明两种帕金森病致病突变会降低 PARL 对 Pink1 的加工，这对发病机制有影响。
