Msp1 Clears Mistargeted Proteins by Facilitating Their Transfer from Mitochondria to the ER
Msp1 Clears Mistargeted Proteins by Facilitating Their Transfer from Mitochondria to the ER
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DOI：
10.1016/j.molcel.2019.07.006
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发表时间：
2019-10-03
期刊：
影响因子：
16
通讯作者：
Endo, Toshiya
中科院分区：
文献类型：
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作者：
Matsumoto, Shunsuke;Nakatsukasa, Kunio;Endo, Toshiya
正常的线粒体功能依赖于其驻留蛋白质的优化组成，而误定位到线粒体的蛋白质需要有效去除。 Msp1 是线粒体外膜 (OM) 中的 AAA-ATP 酶，可促进误定位至 OM 的尾锚定 (TA) 蛋白的降解，但 Msp1 如何与其他因子合作来进行这一过程尚不清楚。在这里，我们证明 Msp1 识别底物 TA 蛋白并促进它们转移到内质网 (ER)。然后，ER 膜中的 Doa10 用 Ubc6 和 Ubc7 泛素化它们。泛素化底物通过胞质溶胶中的另一种 AAA-ATP 酶 Cdc48 从 ER 膜中提取，并与 Ufd1 和 Npl4 一起在胞质溶胶中进行蛋白酶体降解。因此，Msp1 作为提取酶发挥作用，通过促进误定位的 TA 蛋白转移至 ER 进行蛋白质量控制，从而介导清除这些蛋白。
Normal mitochondrial functions rely on optimized composition of their resident proteins, and proteins mistargeted to mitochondria need to be efficiently removed. Msp1, an AAA-ATPase in the mitochondrial outer membrane (OM), facilitates degradation of tail-anchored (TA) proteins mistargeted to the OM, yet how Msp1 cooperates with other factors to conduct this process was unclear. Here, we show that Msp1 recognizes substrate TA proteins and facilitates their transfer to the endoplasmic reticulum (ER). Doa10 in the ER membrane then ubiquitinates them with Ubc6 and Ubc7. Ubiquitinated substrates are extracted from the ER membrane by another AAA-ATPase in the cytosol, Cdc48, with Ufd1 and Npl4 for proteasomal degradation in the cytosol. Thus, Msp1 functions as an extractase that mediates clearance of mistargeted TA proteins by facilitating their transfer to the ER for protein quality control.