LINC00493‐encoded microprotein SMIM26 exerts anti‐metastatic activity in renal cell carcinoma

Article3 April 2023 Source DataTransparent process LINC00493-encoded microprotein SMIM26 exerts anti-metastatic activity in renal cell carcinoma Kun Meng Kun Meng orcid.org/0000-0003-4478-2553 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: Data curation, ​Investigation, Visualization, Writing - original draft Search for more papers by this author Shaohua Lu Shaohua Lu MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Sino-French Hoffmann Institute, School of Basic Medical Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China Contribution: Formal analysis, ​Investigation, Visualization Search for more papers by this author Yu-Ying Li Yu-Ying Li MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Li-Ling Hu Li-Ling Hu MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Jing Zhang Jing Zhang MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Yun Cao Yun Cao Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China Contribution: Resources Search for more papers by this author Yang Wang Corresponding Author Yang Wang [email protected] orcid.org/0000-0001-6440-0204 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: Supervision, Writing - review & editing Search for more papers by this author Chris Zhiyi Zhang Corresponding Author Chris Zhiyi Zhang [email protected] orcid.org/0000-0002-1944-8281 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: Supervision, Writing - review & editing Search for more papers by this author Qing-Yu He Corresponding Author Qing-Yu He [email protected] orcid.org/0000-0003-0503-9492 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: Conceptualization, Funding acquisition, Writing - review & editing Search for more papers by this author Kun Meng Kun Meng orcid.org/0000-0003-4478-2553 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: Data curation, ​Investigation, Visualization, Writing - original draft Search for more papers by this author Shaohua Lu Shaohua Lu MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Sino-French Hoffmann Institute, School of Basic Medical Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China Contribution: Formal analysis, ​Investigation, Visualization Search for more papers by this author Yu-Ying Li Yu-Ying Li MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Li-Ling Hu Li-Ling Hu MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Jing Zhang Jing Zhang MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: ​Investigation Search for more papers by this author Yun Cao Yun Cao Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China Contribution: Resources Search for more papers by this author Yang Wang Corresponding Author Yang Wang [email protected] orcid.org/0000-0001-6440-0204 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: Supervision, Writing - review & editing Search for more papers by this author Chris Zhiyi Zhang Corresponding Author Chris Zhiyi Zhang [email protected] orcid.org/0000-0002-1944-8281 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China Contribution: Supervision, Writing - review & editing Search for more papers by this author Qing-Yu He Corresponding Author Qing-Yu He [email protected] orcid.org/0000-0003-0503-9492 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China Contribution: Conceptualization, Funding acquisition, Writing - review & editing Search for more papers by this author Author Information Kun Meng1,2,†, Shaohua Lu1,3,†, Yu-Ying Li1, Li-Ling Hu1, Jing Zhang1,2, Yun Cao4, Yang Wang *,1, Chris Zhiyi Zhang *,1 and Qing-Yu He *,1,2 1MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China 2The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China 3Sino-French Hoffmann Institute, School of Basic Medical Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China 4Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China † These authors contributed equally to this work *Corresponding author. Tel: +86 20 85223139; E-mail: [email protected] *Corresponding author. Tel: +86 20 85223139; E-mail: [email protected] *Corresponding author. Tel: +86 20 85227039; E-mail: [email protected] EMBO Reports (2023)e56282https://doi.org/10.15252/embr.202256282 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers. Synopsis LINC00493-derived mitochondrial microprotein SMIM26 suppresses clear cell renal cell carcinoma metastasis via interaction with AGK and SLC25A11 to inactivate AKT signaling. SMIM26 is a microprotein encoded by LINC00493 and localizes to mitochondria. Translation of SMIM26 is mediated by the RNA-binding protein PABPC4. SMIM26 interacts with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11. The tripartite complex of SMIM26-AGK-SLC25A11 maintains mitochondrial homeostasis and suppresses ccRCC metastasis. 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