RAB32-USP13轴促进TOM40线粒体定位以驱动非小细胞肺癌进展
The RAB32-USP13 axis facilitates TOM40 mitochondrial localization to promote non-small cell lung cancer progression.
作者
作者单位
- Cancer Center, Renmin Hospital of Wuhan University, Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan, China.
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
- Cancer Center, Renmin Hospital of Wuhan University, Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan, China. zhongbo@whu.edu.cn.
- Cancer Center, Renmin Hospital of Wuhan University, Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan, China. lindandan@whu.edu.cn.
摘要
中文
线粒体是半自主细胞器，其功能关键依赖于核编码蛋白。TOM40是线粒体外膜转位酶（TOM）复合物的核心β-桶蛋白，介导大多数核编码线粒体蛋白的输入。在此，我们显示小GTP酶RAB32促进非小细胞肺癌（NSCLC）细胞中TOM40的线粒体定位和线粒体蛋白稳态。相应地，RAB32敲除导致线粒体功能障碍，并在异种移植和自发性NSCLC小鼠模型中抑制NSCLC进展。我们进一步鉴定出泛素特异性肽酶13（USP13）可去除RAB32上的K48连接多聚泛素链，以防止其蛋白酶体降解。一致地，USP13敲除导致RAB32不稳定，损害TOM40线粒体定位和线粒体功能，并抑制NSCLC进展，这些可通过回补野生型USP13或RAB32恢复，但不能被催化失活的USP13C345A/M664/739E恢复。我们的研究揭示了以前未表征的RAB32-USP13轴在线粒体功能和NSCLC进展中的作用。
English
Mitochondria are semi-autonomous organelles whose functions critically depend on nucleus-encoded proteins. TOM40 is the core β-barrel protein of the translocase of the outer mitochondrial membrane (TOM) complex that mediates the import of most nucleus-encoded mitochondrial proteins. Here, we show that the small GTPase RAB32 facilitates the mitochondrial localization of TOM40 and the mitochondrial protein homeostasis in non-small cell lung cancer (NSCLC) cells. Accordingly, knockout of RAB32 results in mitochondrial dysfunction and inhibits NSCLC progression in xenograft and autochthonous NSCLC mouse models. We further identify ubiquitin-specific peptidase 13 (USP13) that removes the K48-linked polyubiquitin chains from RAB32 to prevent its proteasomal degradation. Consistently, knockout of USP13 causes destabilization of RAB32, impairs TOM40 mitochondrial localization and mitochondrial function, and inhibits NSCLC progression, which are restored by reconstitution of wild-type USP13 or RAB32, but not the catalytically inactive USP13C345A/M664/739E. Our study has revealed a previously uncharacterized RAB32-USP13 axis for mitochondrial functions and NSCLC progression.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 13.6
- 新锐分区
- 1区