Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Mol Cell. 2010 Nov 12;40(3):465-80. doi: 10.1016/j.molcel.2010.10.021.
We show that Ydr049 (renamed VCP/Cdc48-associated mitochondrial stress-responsive--Vms1), a member of an unstudied pan-eukaryotic protein family, translocates from the cytosol to mitochondria upon mitochondrial stress. Cells lacking Vms1 show progressive mitochondrial failure, hypersensitivity to oxidative stress, and decreased chronological life span. Both yeast and mammalian Vms1 stably interact with Cdc48/VCP/p97, a component of the ubiquitin/proteasome system with a well-defined role in endoplasmic reticulum-associated protein degradation (ERAD), wherein misfolded ER proteins are degraded in the cytosol. We show that oxidative stress triggers mitochondrial localization of Cdc48 and this is dependent on Vms1. When this system is impaired by mutation of Vms1, ubiquitin-dependent mitochondrial protein degradation, mitochondrial respiratory function, and cell viability are compromised. We demonstrate that Vms1 is a required component of an evolutionarily conserved system for mitochondrial protein degradation, which is necessary to maintain mitochondrial, cellular, and organismal viability.
我们证明，Ydr049（更名为 VCP/Cdc48 相关的线粒体应激反应蛋白——Vms1），一种未被研究的泛真核蛋白家族的成员，在线粒体应激时从细胞质易位到线粒体。缺乏 Vms1 的细胞显示出进行性的线粒体功能衰竭、对氧化应激的敏感性增加和细胞寿命缩短。酵母和哺乳动物的 Vms1 都能与 Cdc48/VCP/p97 稳定相互作用，后者是泛素/蛋白酶体系统的一个组成部分，在内质网相关蛋白降解（ERAD）中具有明确的作用，其中错误折叠的 ER 蛋白在细胞质中降解。我们表明，氧化应激触发 Cdc48 的线粒体定位，这依赖于 Vms1。当这个系统由于 Vms1 的突变而受损时，依赖于泛素的线粒体蛋白降解、线粒体呼吸功能和细胞活力都会受到损害。我们证明 Vms1 是线粒体蛋白降解的一个必需的进化保守系统的组成部分，它对于维持线粒体、细胞和生物体的活力是必要的。
