MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51
MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51
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MITOL 调节 RMDN3/PTPIP51 的磷脂酸结合活性
DOI：
10.1093/jb/mvab153
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yanagi Shigeru
中科院分区：
文献类型：
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作者：
Ito Naoki;Takahashi Takara;Shiiba Isshin;Nagashima Shun;Inatome Ryoko;Yanagi Shigeru
磷脂从内质网（ER）通过线粒体-内质网接触点（MERCS）转移到线粒体是维持线粒体功能和完整性所必需的。在这里，我们通过使用APEX2的邻近依赖生物素标记，确定了具有磷脂酸（PA）转移活性的RMDN3/PTPIP51是线粒体E3泛素连接酶MITOL/MARCH5的邻近蛋白。我们发现MITOL与RMDN3相互作用并泛素化。突变分析发现RMDN3中的赖氨酸残基89是MITOL泛素化位点。MITOL缺失或RMDN3中赖氨酸89被精氨酸取代显著降低RMDN3的PA结合活性，提示MITOL通过激活RMDN3调节PA向线粒体的转运。我们的研究结果表明，泛素信号调节了MERCS的磷脂转运。
The transfer of phospholipids from the endoplasmic reticulum (ER) to mitochondria via the mitochondria-ER contact site (MERCS) is essential for maintaining mitochondrial function and integrity. Here, we identified RMDN3/PTPIP51, possessing phosphatidic acid (PA)-transfer activity, as a neighbouring protein of the mitochondrial E3 ubiquitin ligase MITOL/MARCH5 by proximity-dependent biotin labelling using APEX2. We found that MITOL interacts with and ubiquitinates RMDN3. Mutational analysis identified lysine residue 89 in RMDN3 as a site of ubiquitination by MITOL. Loss of MITOL or the substitution of lysine 89 to arginine in RMDN3 significantly reduced the PA-binding activity of RMDN3, suggesting that MITOL regulates the transport of PA to mitochondria by activating RMDN3. Our findings imply that ubiquitin signalling regulates phospholipid transport at the MERCS.