Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.
Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China.
Cell Death Dis. 2021 Jun 2;12(6):571. doi: 10.1038/s41419-021-03860-z.
Target of Rapamycin Complex 1 (TORC1) is a master regulator that coordinates nutrient status with cell metabolism. The GTPase-activating protein towards Rags complex 1 (GATOR1) inhibits TORC1 activity and protects cells from damage during periods of stress. Here we characterize multiple pathways that regulate the expression of the GATOR1 component Nprl3 in Drosophila. We determine that the stability of Nprl3 is impacted by the Unassembled Soluble Complex Proteins Degradation (USPD) pathway. In addition, we find that FK506 binding protein 39 (FKBP39)-dependent proteolytic destruction maintains Nprl3 at low levels in nutrient replete conditions. Nutrient starvation abrogates the degradation of the Nprl3 protein and rapidly promotes Nprl3 accumulation. Consistent with a role in promoting the stability of a TORC1 inhibitor, mutations in fkbp39 decrease TORC1 activity and increase autophagy. Finally, we show that the 5'UTR of nprl3 transcripts contain a functional upstream open reading frame (uORF) that inhibits main ORF translation. In summary, our work has uncovered novel mechanisms of Nprl3 regulation and identifies an important role for FKBP39 in the control of cellular metabolism.
雷帕霉素靶蛋白复合物 1（TORC1）是一种主调控因子，它协调营养状态与细胞代谢。Rags 复合物 1（GATOR1）的 GTP 酶激活蛋白抑制 TORC1 活性，并在应激期间保护细胞免受损伤。在这里，我们描述了调节果蝇 GATOR1 成分 Nprl3 表达的多种途径。我们确定 Nprl3 的稳定性受未组装可溶性复合物蛋白降解（USPD）途径的影响。此外，我们发现 FK506 结合蛋白 39（FKBP39）依赖性蛋白水解破坏在营养丰富的条件下将 Nprl3 维持在低水平。营养饥饿会破坏 Nprl3 蛋白的降解，并迅速促进 Nprl3 的积累。与促进 TORC1 抑制剂稳定性的作用一致，fkbp39 的突变会降低 TORC1 活性并增加自噬。最后，我们表明 nprl3 转录本的 5'UTR 含有一个功能性的上游开放阅读框（uORF），该框抑制主要 ORF 的翻译。总之，我们的工作揭示了 Nprl3 调节的新机制，并确定了 FKBP39 在控制细胞代谢中的重要作用。
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