Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins
Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins
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DOI：
10.15252/embj.201487943
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发表时间：
2014-07-17
期刊：
影响因子：
11.4
通讯作者：
Rutter, Jared
中科院分区：
文献类型：
--
作者：
Chen, Yu-Chan;Umanah, George K. E.;Rutter, Jared
大多数ER靶向的尾锚定（TA）蛋白通过尾锚定蛋白的引导进入（GET）系统插入膜中。该系统的破坏导致TA蛋白的子集错误定位于线粒体。我们发现，AAA+ ATP酶Msp 1限制了线粒体上错误定位的TA蛋白的积累。当GET系统受损时，MSP 1的缺失导致Pex 15和Gos 1 TA蛋白在线粒体上积累。可能由于未能提取错误定位的TA蛋白，具有MSP 1基因和GET系统的组合突变的酵母表现出强烈的协同生长缺陷和严重的线粒体损伤，包括线粒体DNA和蛋白质的损失以及异常的线粒体形态。与酵母Msp 1类似，人ATAD 1限制了PEX 26和GOS 28的线粒体错误定位，PEX 26和GOS 28分别是Pex 15和Gos 1的直系同源物。ATAD 1（-/-）小鼠组织中GOS 28蛋白水平也增加。因此，我们建议，酵母Msp 1和哺乳动物ATAD 1的线粒体蛋白质质量控制系统的保守成员，可能会促进提取和降解的错误定位的TA蛋白，以维持线粒体的完整性。
The majority of ER-targeted tail-anchored (TA) proteins are inserted into membranes by the Guided Entry of Tail-anchored protein (GET) system. Disruption of this system causes a subset of TA proteins to mislocalize to mitochondria. We show that the AAA+ ATPase Msp1 limits the accumulation of mislocalized TA proteins on mitochondria. Deletion of MSP1 causes the Pex15 and Gos1 TA proteins to accumulate on mitochondria when the GET system is impaired. Likely as a result of failing to extract mislocalized TA proteins, yeast with combined mutation of the MSP1 gene and the GET system exhibit strong synergistic growth defects and severe mitochondrial damage, including loss of mitochondrial DNA and protein and aberrant mitochondrial morphology. Like yeast Msp1, human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28, orthologs of Pex15 and Gos1, respectively. GOS28 protein level is also increased in ATAD1(-/-) mouse tissues. Therefore, we propose that yeast Msp1 and mammalian ATAD1 are conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity.