Journal
CELL RESEARCH
Volume 29, Issue 2, Pages 136-150Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/s41422-018-0120-9
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Funding
- National Key Research and Development Program of China [2016YFC0902102]
- National Natural Science Foundation of China [81625019, 91440104,91519322, 31600725, 31830053, 31801177]
- Science Technology Commission of Shanghai Municipality [16JC1404500]
- Shanghai Sailing Program [18YF1419500, 18YF1419300]
- Fundamental Research Funds for the Central Universities [22120180043, 22120170212, 22120180045]
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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.
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