Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
Cell Chem Biol. 2022 Jun 16;29(6):1037-1045.e4. doi: 10.1016/j.chembiol.2022.02.006. Epub 2022 Mar 15.
The small GTPase Ras homolog enriched in brain (Rheb) plays a critical role in activating the mechanistic target of rapamycin complex 1 (mTORC1), a signaling hub that regulates various cellular functions. We recently observed nuclear mTORC1 activity, raising an intriguing question as to how Rheb, which is known to be farnesylated and localized to intracellular membranes, regulates nuclear mTORC1. In this study, we found that active Rheb is present in the nucleus and required for nuclear mTORC1 activity. We showed that inhibition of farnesyltransferase reduced cytosolic, but not nuclear, mTORC1 activity. Furthermore, a farnesylation-deficient Rheb mutant, with preferential nuclear localization and specific lysosome tethering, enables nuclear and cytosolic mTORC1 activities, respectively. These data suggest that non-farnesylated Rheb is capable of interacting with and activating mTORC1, providing mechanistic insights into the molecular functioning of Rheb as well as regulation of the recently observed, active pool of nuclear mTORC1.
富含于脑的小 GTP 酶 Ras 同源物（Rheb）在激活雷帕霉素靶蛋白复合物 1（mTORC1）中起着关键作用，mTORC1 是一个信号枢纽，调节各种细胞功能。我们最近观察到核 mTORC1 的活性，这提出了一个有趣的问题，即众所周知被法呢基化并定位于细胞内膜的 Rheb 如何调节核 mTORC1。在这项研究中，我们发现活性 Rheb 存在于核内，并且是核 mTORC1 活性所必需的。我们表明，法尼基转移酶抑制剂降低了细胞质，但不是核内，mTORC1 活性。此外，具有优先核定位和特定溶酶体锚定的法尼基化缺陷 Rheb 突变体分别能够使核和细胞质 mTORC1 活性。这些数据表明，非法尼基化的 Rheb 能够与 mTORC1 相互作用并激活它，为 Rheb 的分子功能以及最近观察到的核 mTORC1 的活性池的调节提供了机制上的见解。
