Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
Cells. 2024 Oct 30;13(21):1795. doi: 10.3390/cells13211795.
The multiprotein Target of Rapamycin (TOR) Complex 1 (TORC1) is a serine/threonine kinase that stimulates anabolic metabolism and suppresses catabolism. Deregulation of TORC1 is implicated in various human pathologies, including cancer, epilepsy, and neurodegenerative disorders. The Gap Activity Towards Rags (GATOR) complex contains two subcomplexes: GATOR1, which inhibits TORC1 activity; and GATOR2, which counteracts GATOR1s function. Structural and biochemical studies have elucidated how GATOR1 regulates TORC1 activity by acting as a GTPase activating protein for Rag GTPase. However, while cryogenic electron microscopy has determined that the structure of the multi-protein GATOR2 complex is conserved from yeast to humans, how GATOR2 inhibits GATOR1 remains unclear. Here, we describe recent whole-animal studies in Drosophila that have yielded novel insights into GATOR2 function, including identifying a novel role for the GATOR2 subunit WDR59, redefining the core proteins sufficient for GATOR2 activity, and defining a TORC1-independent role for GATOR2 in the regulation of the lysosomal autophagic endomembrane system. Additionally, the recent characterization of a novel methionine receptor in Drosophila that acts through the GATOR2 complex suggests an attractive model for the evolution of species-specific nutrient sensors. Research on GATOR2 function in Drosophila highlights how whole-animal genetic models can be used to dissect intracellular signaling pathways to identify tissue-specific functions and functional redundancies that may be missed in studies confined to rapidly proliferating cell lines.
雷帕霉素靶蛋白（TOR）复合物 1（TORC1）是一种丝氨酸/苏氨酸激酶，可刺激合成代谢并抑制分解代谢。TORC1 的失调与多种人类疾病有关，包括癌症、癫痫和神经退行性疾病。间隙活性 towards Rags（GATOR）复合物包含两个亚复合物：GATOR1，抑制 TORC1 活性；和 GATOR2，抵消 GATOR1 的功能。结构和生化研究阐明了 GATOR1 如何通过作为 Rag GTPase 的 GTP 酶激活蛋白来调节 TORC1 活性。然而，虽然低温电子显微镜已经确定了多蛋白 GATOR2 复合物的结构从酵母到人类都是保守的，但 GATOR2 如何抑制 GATOR1 仍然不清楚。在这里，我们描述了最近在果蝇中的全动物研究，这些研究为 GATOR2 功能提供了新的见解，包括确定 GATOR2 亚基 WDR59 的新作用、重新定义 GATOR2 活性所必需的核心蛋白，以及定义 GATOR2 在溶酶体自噬内膜系统调节中的 TORC1 独立作用。此外，最近在果蝇中鉴定出一种新型蛋氨酸受体，该受体通过 GATOR2 复合物发挥作用，这为物种特异性营养传感器的进化提供了一个有吸引力的模型。关于 GATOR2 在果蝇中的功能研究强调了如何使用全动物遗传模型来剖析细胞内信号通路，以确定组织特异性功能和功能冗余，这些功能和功能冗余在仅限于快速增殖细胞系的研究中可能会被忽略。
