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.

大脑中富集的小 GTPase Ras 同系物 (Rheb) 在激活雷帕霉素复合物 1 (mTORC1) 的机制靶标方面起着关键作用，mTORC1 是调节各种细胞功能的信号中枢。我们最近观察到核 mTORC1 活性，提出了一个有趣的问题，即 Rheb（已知被法呢基化并定位于细胞内膜）如何调节核 mTORC1。在这项研究中，我们发现活性 Rheb 存在于细胞核中并且是核 mTORC1 活性所必需的。我们发现抑制法尼基转移酶会降低细胞溶质，但不会降低细胞核的 mTORC1 活性。此外，法尼基化缺陷型 Rheb 突变体具有优先核定位和特异性溶酶体束缚，分别可实现核和胞质 mTORC1 活性。