2. Academic Validation
  3. RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis

RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis

  • EMBO J. 2025 Feb;44(4):1185-1219. doi: 10.1038/s44318-024-00353-5.
Fengwu Zhang 1 2 3,  Xiufang Xiong 1 2 3,  Zhijian Li 1 2 3,  Haibo Wang 1 2 3,  Weilin Wang 1 2,  Yongchao Zhao 4 5 6,  Yi Sun 7 8 9 10 11 12 13
Affiliations

Affiliations

  • 1 Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
  • 2 Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, 310009, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 4 Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. yongchao@zju.edu.cn.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 6 Cancer Center, Zhejiang University, 310058, Hangzhou, China. yongchao@zju.edu.cn.
  • 7 Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China. yisun@zju.edu.cn.
  • 8 Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, 310009, Hangzhou, China. yisun@zju.edu.cn.
  • 9 Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. yisun@zju.edu.cn.
  • 10 Cancer Center, Zhejiang University, 310058, Hangzhou, China. yisun@zju.edu.cn.
  • 11 Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, Hangzhou, China. yisun@zju.edu.cn.
  • 12 Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, 310053, Hangzhou, China. yisun@zju.edu.cn.
  • 13 Institute of Fundamental and Transdisciplinary Research Zhejiang University, Hangzhou, China. yisun@zju.edu.cn.
PMID: 39762645 DOI: 10.1038/s44318-024-00353-5
Abstract

Small GTPase RHEB is a well-known mTORC1 Activator, whereas neddylation modifies cullins and non-cullin substrates to regulate their activity, subcellular localization and stability. Whether and how RHEB is subjected to neddylation modification remains unknown. Here, we report that RHEB is a substrate of NEDD8-conjugating E2 Enzyme UBE2F. In Cell Culture, UBE2F depletion inactivates mTORC1, inhibiting cell cycle progression, cell growth and inducing Autophagy. Mechanistically, UBE2F cooperates with E3 Ligase SAG in neddylation of RHEB at K169 to enhance its lysosome localization and GTP-binding affinity. Furthermore, liver-specific Ube2f knockout attenuates steatosis and tumorigenesis induced by PTEN loss in an mTORC1-dependent manner, suggesting a causal role of UBE2F in liver tumorigenesis. Finally, UBE2F expression levels and mTORC1 activity correlate with patient survival in hepatocellular carcinoma. Collectively, our study identifies RHEB as neddylation substrate of the UBE2F-SAG axis, and highlights the UBE2F-SAG axis as a potential target for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma.

Keywords

Liver Steatosis and Tumorigenesis; Neddylation; RHEB; UBE2F; mTORC1.

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