Matsumoto Shunsuke, Kogure Yoshiki, Ono Suzuka, Numata Tomoyuki, Endo Toshiya
Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan.
Faculty of Life Sciences, Kyoto Sangyo University, Japan.
FEBS J. 2025 Aug;292(16):4289-4313. doi: 10.1111/febs.70132. Epub 2025 May 9.
Yeast Msp1 is a dual-localized AAA-ATPase on the mitochondrial outer membrane (OM) and peroxisomal membrane. We previously showed that Msp1 transfers mistargeted tail-anchored (TA) proteins from mitochondria to the endoplasmic reticulum (ER) for degradation or delivery to their original destinations. However, the mechanism by which Msp1 in mitochondria and peroxisomes handles authentic peroxisomal TA proteins remains unclear. We show that newly synthesized Pex15 is targeted to peroxisomes primarily via the Pex19- and Pex3-dependent pathway. Mistargeted Pex15 on the mitochondrial OM is extracted by mitochondrial Msp1 and transferred to the ER via the guided-entry of TA proteins pathway for degradation or to peroxisomes via the Pex19-Pex3 pathway. Intriguingly, endogenous Pex15 localized in peroxisomes is also extracted from the membranes by peroxisomal Msp1 but returns to peroxisomes via the Pex19-Pex3 pathway. These results suggest that correct Pex15 localization to peroxisomes relies on not only the initial targeting by Pex19-Pex3 but also the constant re-routing by Msp1 and Pex19-Pex3.
酵母Msp1是一种定位于线粒体外膜（OM）和过氧化物酶体膜的双功能AAA-ATP酶。我们之前发现，Msp1可将错误定位的尾锚定（TA）蛋白从线粒体转运至内质网（ER）进行降解或转运至其原始目的地。然而，线粒体和过氧化物酶体中的Msp1处理真正的过氧化物酶体TA蛋白的机制仍不清楚。我们发现，新合成的Pex15主要通过依赖Pex19和Pex3的途径靶向过氧化物酶体。线粒体外膜上错误定位的Pex15可被线粒体Msp1提取，并通过TA蛋白的引导进入途径转运至内质网进行降解，或通过Pex19-Pex3途径转运至过氧化物酶体。有趣的是，定位于过氧化物酶体的内源性Pex15也可被过氧化物酶体Msp1从膜上提取，但通过Pex19-Pex3途径返回过氧化物酶体。这些结果表明，Pex15正确定位于过氧化物酶体不仅依赖于Pex19-Pex3的初始靶向作用，还依赖于Msp1和Pex19-Pex3的持续重新定向作用。
