The RAB32-USP13 axis facilitates TOM40 mitochondrial localization to promote non-small cell lung cancer progression
Hong-Xu Li1, Yi-Ting Wei1, Hu Gan1
1Cancer 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.
Abstract:
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.
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