The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover.
The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover.
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DOI：
10.1091/mbc.e10-09-0748
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发表时间：
2011-02-01
影响因子：
3.3
通讯作者：
Karbowski M
中科院分区：
文献类型：
--
作者：
Xu S;Peng G;Wang Y;Fang S;Karbowski M
最近的研究揭示了Ub/蛋白酶体系统在OMM相关蛋白的调节和周转中的作用。所提供的数据表明，AAA-ATP酶，p97，是所需的Mcl 1和Mfn 1，两个无关的OMM蛋白的蛋白酶体降解，并建立p97作为一个新的和必不可少的一部分的OMM蛋白降解途径。最近的研究揭示了泛素/蛋白酶体系统在线粒体外膜（OMM）相关蛋白的调节和周转中的作用。尽管已经鉴定了该过程所需的几种分子组分，但OMM相关蛋白的蛋白酶体依赖性降解机制目前尚不清楚。我们发现，AAA-ATPase，p97，是所需的Mcl 1和Mfn 1，两个不相关的OMM蛋白质的半衰期短的蛋白酶体降解。一些生化测定，以及成像的变化，在本地化的光活化的GFP融合的Mcl 1，显示p97调节的逆转录易位的Mcl 1从线粒体到细胞质，之前，或同时，蛋白酶体降解。Mcl 1从OMM的逆转位依赖于p97的ATP酶结构域的活性。此外，p97介导的Mcl 1的逆转录易位可以在体外重演，证实了p97的直接线粒体作用。我们的研究结果建立p97作为一种新的和必要的组成部分的OMM相关的蛋白质降解途径。
Recent studies have revealed a role for the Ub/proteasome system in the regulation and turnover of OMM-associated proteins. The data presented show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins, and establishes p97 as a novel and essential part of the OMM-protein degradation pathway. Recent studies have revealed a role for the ubiquitin/proteasome system in the regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Although several molecular components required for this process have been identified, the mechanism of proteasome-dependent degradation of OMM-associated proteins is currently unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, revealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confirming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway.