Mitochondrial membrane remodelling regulated by a conserved rhomboid protease
Mitochondrial membrane remodelling regulated by a conserved rhomboid protease
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DOI：
10.1038/nature01633
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发表时间：
2003-05-29
期刊：
影响因子：
64.8
通讯作者：
Freeman, M
中科院分区：
文献类型：
--
作者：
McQuibban, GA;Saurya, S;Freeman, M
菱形蛋白是激活果蝇表皮生长因子受体（EGFR）信号的膜内丝氨酸蛋白酶(1)。菱形体在整个进化过程中是保守的（2-5），即使在真核生物中，它们在没有egfr的物种中存在意味着它们必须具有额外的作用。本文报道了酿酒酵母有两个菱形体，分别命名为Rbd1p和Rbd2p。RBD1缺失导致呼吸缺陷；与此一致的是，Rbd1p定位于线粒体内膜，突变细胞破坏了线粒体。我们已经确定了Rbd1p的两个底物：细胞色素c过氧化物酶（Ccp1p）；和一个动力蛋白样GTPase (Mgm1p)，参与线粒体膜融合（6-10）。Rbd1p突变体与Mgm1p突变体难以区分，这表明Mgm1p是Rbd1p的关键底物，并解释了rbd1Delta线粒体表型。我们的数据表明，线粒体膜重塑是由Mgm1p的切割调节的，并表明菱形体的膜内蛋白水解控制着除信号传导外的细胞过程。此外，线粒体菱形在真核生物中是保守的，哺乳动物的同源物PARL（11）拯救了酵母突变体，这表明这些蛋白代表了功能保守的菱形蛋白酶亚类。
Rhomboid proteins are intramembrane serine proteases that activate epidermal growth factor receptor (EGFR) signalling in Drosophila(1). Rhomboids are conserved throughout evolution(2-5), and even in eukaryotes their existence in species with no EGFRs implies that they must have additional roles. Here we report that Saccharomyces cerevisiae has two rhomboids, which we have named Rbd1p and Rbd2p. RBD1 deletion results in a respiratory defect; consistent with this, Rbd1p is localized in the inner mitochondrial membrane and mutant cells have disrupted mitochondria. We have identified two substrates of Rbd1p: cytochrome c peroxidase (Ccp1p); and a dynamin-like GTPase (Mgm1p), which is involved in mitochondrial membrane fusion(6-10). Rbd1p mutants are indistinguishable from Mgm1p mutants, indicating that Mgm1p is a key substrate of Rbd1p and explaining the rbd1Delta mitochondrial phenotype. Our data indicate that mitochondrial membrane remodelling is regulated by cleavage of Mgm1p and show that intramembrane proteolysis by rhomboids controls cellular processes other than signalling. In addition, mitochondrial rhomboids are conserved throughout eukaryotes and the mammalian homologue, PARL(11), rescues the yeast mutant, suggesting that these proteins represent a functionally conserved subclass of rhomboid proteases.