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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\n                    <jats:italic>Ube2f<\/jats:italic>\n                    knockout attenuates steatosis and tumorigenesis induced by\n                    <jats:italic>Pten<\/jats:italic>\n                    loss in an mTORC1-dependent manner, suggesting a causal role of UBE2F in liver tumorigenesis. Finally,\u00a0UBE2F 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.\n                  <\/jats:p>","DOI":"10.1038\/s44318-024-00353-5","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T07:44:10Z","timestamp":1736149450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis"],"prefix":"10.1038","volume":"44","author":[{"given":"Fengwu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufang","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-5817","authenticated-orcid":false,"given":"Zhijian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2416-9153","authenticated-orcid":false,"given":"Haibo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4610-4182","authenticated-orcid":false,"given":"Yongchao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5841-4287","authenticated-orcid":false,"given":"Yi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"353_CR1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.canlet.2015.08.012","volume":"369","author":"MK Altman","year":"2015","unstructured":"Altman MK, Alshamrani AA, Jia W, Nguyen HT, Fambrough JM, Tran SK, Patel MB, Hoseinzadeh P, Beedle AM, Murph MM (2015) Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells. 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