MassIVE MSV000096912

Complete Public PXD060069

Oxidation of Retromer Complex controls Mitochondrial Translation

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Description

Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration. The mitochondrial electron transport chain is appreciated as a key regulator of ROS stoichiometry in cells. However, the pathways that sense and regulate ROS levels more broadly remain to be fully elucidated. Here, systematic base-editor and computational screens identify VPS35, a member of the Retromer trafficking complex, as a cytosolic ROS sensor. Mechanistically, we find that VPS35 C653/C673 regulates compartmentalized mitochondrial translation by disrupting the plasma membrane localization of SLC7A1, leading to dramatic resistance against ROS-generating anti-cancer agents including cisplatin. Our study describes the regulation of compartmentalized translation and cellular ROS homeostasis by a single amino acid within vesicular trafficking machinery, supporting the long-standing hypothesis that mitochondrial ROS is implicated in cisplatin resistance. We anticipate that the approaches employed herein may template a generalizable method for the identification of functional ROS targets and sensors under various biological contexts. [doi:10.25345/C58P5VN52] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: K562 ; Plasma Membrane ; Anti-cancer Agents ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Liron Bar-Peled, Massachusetts General Hospital Cancer Center, USA
Submitting User: hbc8
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