Constitutively Active Rheb Regulates Nuclear mTORC1 Activity and Function

• Published in: The FASEB journal 2020-04, Vol.34 (S1), p.1-1
• Main Authors: Zhong, Yanghao, Zhou, Xin, Guan, Kun-Liang, Zhang, Jin
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2020.34.s1.07130

Abstract only mTOR complex 1 (mTORC1) is a key signaling hub that regulates many fundamental cellular processes, including macromolecule synthesis, proliferation and autophagy. Abnormalities in mTORC1 signaling pathway are implicated in pathological conditions such as the progression of cancer and diabetes. Diverse signals can regulate mTORC1 activity and spatiotemporal regulation of mTORC1 has been suggested to play a crucial role in achieving high signaling specificity. Previously, a fluorescent mTORC1 activity reporter (TORCAR) revealed nuclear mTORC1 activity in live cells. However, the specific mechanisms that regulate nuclear mTORC1 activity and the functionalities of nuclear mTORC1 are unclear. In this study, we investigated whether and how Rheb, a key mTORC1 activator, is involved in regulating growth factor induced nuclear mTORC1 activity. First, we showed knockdown of Rheb largely suppressed growth factor stimulated nuclear TORCAR response. We further showed that Tuberous sclerosis complex subunit 2 (TSC2), a GAP for Rheb, was absent from the nucleus, and overexpressing TSC2 exclusively in the nucleus significantly inhibited nuclear TORCAR response, suggesting that Rheb is constitutively active in the nucleus. Our experimental data established a model of nuclear mTORC1 regulation and suggested Rheb is indispensable for nuclear mTORC1 activity. Our ongoing experiments include using phosphoproteomic experiments to identify the substrates of nuclear mTORC1 and RNAseq experiments to examine the emerging role of nuclear mTORC1 in controlling transcription in the nucleus.