Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

• Published in: Cell research Vol. 29; no. 2; pp. 136 - 150
• Main Authors: Deng, Lu, Chen, Lei, Zhao, Linlin, Xu, Yan, Peng, Xiaoping, Wang, Xinbo, Ding, Lin, Jin, Jiali, Teng, Hongqi, Wang, Yanming, Pan, Weijuan, Yu, Fei, Liao, Lujian, Li, Li, Ge, Xin, Wang, Ping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 38; 42; 42/89; 45/70; 631/337/458/582; 631/80/458/582; 82; 82/1; 82/51; 82/83; 96; 96/31; Activation; AKT protein; Animals; Biomedical and Life Sciences; Cell Biology; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Gene Knockout Techniques; Growth factors; Guanosine triphosphatases; Guanosine triphosphate; HCT116 Cells; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Life Sciences; Lysosomes - metabolism; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; Mice, Knockout; Mice, Nude; Phosphorylation; Rapamycin; Ras Homolog Enriched in Brain Protein - genetics; Ras Homolog Enriched in Brain Protein - metabolism; Regulatory mechanisms (biology); Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR protein; Transfection; Tumor Burden - drug effects; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitination; Xenograft Model Antitumor Assays; Activator Rheb; mTORC1 Activity; Monoubiquitination; Endogenous Ubiquitination; Nucleotide-bound State
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-018-0120-9

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) plays a key role in the integration of various environmental signals to regulate cell growth and metabolism. mTORC1 is recruited to the lysosome where it is activated by its interaction with GTP-bound Rheb GTPase. However, the regulatory mechanism of Rheb activity remains largely unknown. Here, we show that ubiquitination governs the nucleotide-bound status of Rheb. Lysosome-anchored E3 ligase RNF152 catalyzes Rheb ubiquitination and promotes its binding to the TSC complex. EGF enhances the deubiquitination of Rheb through AKT-dependent USP4 phosphorylation, leading to the release of Rheb from the TSC complex. Functionally, ubiquitination of Rheb is linked to mTORC1-mediated signaling and  consequently regulates tumor growth. Thus, we propose a mechanistic model whereby Rheb–mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively.