Highlights d Amino acid signaling regulates RagA ubiquitination d RNF152 targets RagA for K63-linked ubiquitination d RagA ubiquitination by RNF152 inhibits RagA and mTORC1 activation d RagA ubiquitination promotes its binding to GATOR1
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.
A cold atmospheric-pressure plasma, which has been widely used for biomedical applications, may potentially affect the cell cycle and cause cell apoptosis. In this paper, a human hepatocellular carcinoma cell (HepG2) is treated by a singleelectrode plasma jet device. Further investigation by using flow cytometric analysis demonstrates that plasma treatment increases the percentage of apoptotic cells being associated with cell cycle arrest at the G2/M phase. Moreover, the reverse transcription polymerase chain reaction assay shows that the cyclin B1 and Cdc2 are decreased at the transcription level after plasma treatment, while the expression of the p21 Cdk inhibitor, as well as that of tumor suppressor p53, is enhanced. On the other hand, the levels of certain pro-or antiapoptotic genes are checked, and the experimental results suggest that the plasma induces apoptosis by shifting the Bax/Bcl-2 ratio to trigger HepG2 cell apoptosis. The results of the present investigation indicate that the plasma jet device may have potential therapeutic activities, such as sterilization of living tissue and tumor therapy of the postoperative treatment process.
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