The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster.
The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster.
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DOI：
10.1534/g3.116.035337
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发表时间：
2016-12-07
期刊：
影响因子：
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通讯作者：
Lilly MA
中科院分区：
文献类型：
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作者：
Wei Y;Reveal B;Cai W;Lilly MA
TORC1调节代谢和生长，以响应大量的上游输入。进化上保守的三聚体GATOR 1复合物响应于氨基酸限制而抑制TORC 1活性。在人类中，GATOR 1复合物与多种病理学有关，包括癌症和遗传性癫痫。然而，GATOR 1在动物生理学中的确切作用在很大程度上仍然不确定。在这里，我们的特点无效突变体的GATOR 1组件nprl2，nprl3，和iml1果蝇。我们证明，所有三种突变体都具有不适当的高基线水平的TORC 1活性和降低的成人生存能力。与增加的TORC 1活性一致，GATOR 1突变体表现出细胞生长的细胞自主增加。值得注意的是，逃逸者nprl2和nprl3突变体成虫具有严重的运动缺陷。与系统代谢调节中的非自主作用一致，在脂肪体、营养储存器官和血细胞中表达Nprl3蛋白而不是肌肉和神经元中表达Nprl3蛋白拯救了nprl3突变体的运动性。最后，我们发现nprl2和nprl3突变体不能激活自噬反应的氨基酸限制，是非常敏感的氨基酸和完全饥饿。因此，在果蝇中，除了维持基线水平的TORC 1活性外，GATOR 1复合物在对营养胁迫的反应中保留了关键作用。总之，TORC 1抑制剂GATOR 1对果蝇的发育和生理学的多个方面做出了贡献。
TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionarily conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here, we characterize null mutants of the GATOR1 components nprl2, nprl3, and iml1 in Drosophila melanogaster. We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability. Consistent with increased TORC1 activity, GATOR1 mutants exhibit a cell autonomous increase in cell growth. Notably, escaper nprl2 and nprl3 mutant adults have a profound locomotion defect. In line with a nonautonomous role in the regulation of systemic metabolism, expressing the Nprl3 protein in the fat body, a nutrient storage organ, and hemocytes but not muscles and neurons rescues the motility of nprl3 mutants. Finally, we show that nprl2 and nprl3 mutants fail to activate autophagy in response to amino acid limitation and are extremely sensitive to both amino acid and complete starvation. Thus, in Drosophila, in addition to maintaining baseline levels of TORC1 activity, the GATOR1 complex has retained a critical role in the response to nutrient stress. In summary, the TORC1 inhibitor GATOR1 contributes to multiple aspects of the development and physiology of Drosophila.