Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Lu Deng; Lei Chen; Linlin Zhao; Yan Xu; Xiaoping Peng; Xinbo Wang; Lin Ding; Jiali Jin; Hongqi Teng; Yanming Wang; Weijuan Pan; Fei Yu; Lujian Liao; Li Li; Xin Ge; Ping Wang

doi:10.1038/s41422-018-0120-9

Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Cell Res. 2019 Feb;29(2):136-150. doi: 10.1038/s41422-018-0120-9. Epub 2018 Dec 4.

Authors

Lu Deng¹, Lei Chen^{1

2

3}, Linlin Zhao¹, Yan Xu⁴, Xiaoping Peng¹, Xinbo Wang¹, Lin Ding¹, Jiali Jin¹, Hongqi Teng¹, Yanming Wang¹, Weijuan Pan⁴, Fei Yu¹, Lujian Liao⁴, Li Li⁵, Xin Ge⁶, Ping Wang⁷

Affiliations

¹ Tongji Unviersity Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, School of Life Sciences and Technolog, Tongji University, 200092, Shanghai, China.
² Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
³ College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China.
⁴ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241, Shanghai, China.
⁵ Institute of Aging Research, Hangzhou Normal University, 311121, Hangzhou, China.
⁶ Department of Clinical Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China.
⁷ Tongji Unviersity Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, School of Life Sciences and Technolog, Tongji University, 200092, Shanghai, China. wangp@tongji.edu.cn.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / metabolism
Gene Knockout Techniques
HCT116 Cells
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins / metabolism*
Lysosomes / metabolism
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Mice, Knockout
Mice, Nude
Ras Homolog Enriched in Brain Protein / genetics
Ras Homolog Enriched in Brain Protein / metabolism*
Sirolimus / pharmacology
Sirolimus / therapeutic use
Transfection
Tumor Burden / drug effects
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitin-Specific Proteases / genetics
Ubiquitination*
Xenograft Model Antitumor Assays

Substances

Intercellular Signaling Peptides and Proteins
RHEB protein, human
Ras Homolog Enriched in Brain Protein
USP4 protein, human
Usp4 protein, mouse
RNF152 protein, human
Ubiquitin-Protein Ligases
Mechanistic Target of Rapamycin Complex 1
Ubiquitin-Specific Proteases
Sirolimus