环结构域对于 GATOR2 依赖性 mTORC1 激活是必需的。
Ring domains are essential for GATOR2-dependent mTORC1 activation.
机构信息
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China.
出版信息
Mol Cell. 2023 Jan 5;83(1):74-89.e9. doi: 10.1016/j.molcel.2022.11.021. Epub 2022 Dec 16.
The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.
GATOR2-GATOR1 信号轴对于氨基酸依赖的 mTORC1 激活至关重要。然而，GATOR2 复合物的分子功能仍然未知。在这里，我们报告说，破坏 Mios、WDR24 或 WDR59 的环结构域完全阻碍了氨基酸介导的 mTORC1 激活。在机制上，Mios 的环结构域通过与 WDR59 和 WDR24 的环结构域相互作用，充当维持 GATOR2 完整性的枢纽，其破坏导致 WDR24 的自我泛素化。从生理上讲，亮氨酸刺激将 Sestrin2 从 WDR24 的环结构域中解离出来，并使其能够与 UBE2D3 结合，随后对 NPRL2 进行泛素化，有助于 GATOR2 介导的 GATOR1 失活。因此，WDR24 的缺失或环结构域的缺失阻止了 mTORC1 的激活，导致在小鼠中 E10.5 时出现严重的生长缺陷和胚胎致死。因此，我们的发现表明，环结构域对于 GATOR2 将氨基酸可用性传递给 mTORC1 是必不可少的，并进一步揭示了营养感应在胚胎发育过程中的重要性。
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