Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2019,（2）
• 页码范围: 136-150
• 页数: 15页
• 语种: 英文

摘要

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.