PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis
PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis
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DOI：
10.1038/ncb3488
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发表时间：
2017-04-01
影响因子：
21.3
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
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作者：
Saita, Shotaro;Nolte, Hendrik;Langer, Thomas
线粒体通过释放促凋亡蛋白来驱动细胞凋亡，促凋亡蛋白促进胞质溶胶中的半胱天冬酶活化。菱形蛋白酶PARL是内膜中的膜内切割肽酶，调节线粒体自噬并在细胞凋亡中起不明确的作用。在这里，我们采用基于PARL的蛋白质组学来定义其底物谱。我们的数据确定了线粒体促凋亡蛋白Smac（也称为DIABLO）作为PARL底物。在凋亡细胞中，Smac被释放到胞质溶胶中，并通过抑制凋亡抑制剂（IAP）来促进半胱天冬酶活性。PARL对Smac的膜内切割产生了一个氨基末端IAP结合基序，这是其凋亡活性所必需的。PARL的丧失损害Smac的蛋白水解成熟，其不能结合XIAP。Smac肽模拟物、XIAP的下调或裂解的Smac的胞质表达恢复PARL缺陷细胞中的凋亡。我们的研究结果揭示了PARL的促凋亡功能，并确定PARL介导的Smac加工和细胞色素c释放促进OPA1依赖的嵴重塑作为两个独立的促凋亡途径在线粒体。
Mitochondria drive apoptosis by releasing pro-apoptotic proteins that promote caspase activation in the cytosol. The rhomboid protease PARL, an intramembrane cleaving peptidase in the inner membrane, regulates mitophagy and plays an ill-defined role in apoptosis. Here, we employed PARL-based proteomics to define its substrate spectrum. Our data identified the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) as a PARL substrate. In apoptotic cells, Smac is released into the cytosol and promotes caspase activity by inhibiting inhibitors of apoptosis (IAPs). Intramembrane cleavage of Smac by PARL generates an amino-terminal IAP-binding motif, which is required for its apoptotic activity. Loss of PARL impairs proteolytic maturation of Smac, which fails to bind XIAP. Smac peptidomimetics, downregulation of XIAP or cytosolic expression of cleaved Smac restores apoptosis in PARL-deficient cells. Our results reveal a pro-apoptotic function of PARL and identify PARL-mediated Smac processing and cytochrome c release facilitated by OPA1-dependent cristae remodelling as two independent pro-apoptotic pathways in mitochondria.