Cell Cycle Regulation In Oogenesis

卵子发生中的细胞周期调控

• 批准号: 10913218
• 负责人: MARY A LILLY
• 金额: $ 195.27万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913218
• 关键词: Autophagocytosis; Brain; Cell Cycle; Cell Cycle Regulation; Complex; Congenital Abnormality; Data; Defect; Degradation Pathway; Development; Drosophila genus; Drosophila melanogaster; Event; Eye; Fat Body; Female; Gametogenesis; Germ Cells; Goals; Growth; Human; Human Pathology; Laboratories; Meiosis; Metabolic; Metabolism; Modeling; Mutation; Nutrient; Oocytes; Oogenesis; Ovary; Proteins; Regulation; Regulatory Pathway; Reproductive Biology; Reproductive Medicine; Role; Signal Pathway; Spontaneous abortion; Starvation; Tacrolimus Binding Proteins; Work; chromosome missegregation; egg; event cycle; hormonal signals; imaginal disc; in vivo; inhibitor; model organism; novel; programs; protein complex; tissue/cell culture

The dysregulation of the TORC1 contributes to a wide array of human pathologies. Over the last year, we defined several regulatory pathways that control the abundance of components of the multiprotein TORC1 inhibitor Gap Activity Towards Rags 1 (GATOR1). The GATOR1 complex is composed of three proteins Nprl2, Nprl3 and Iml1. We determine that in Drosophila the stability of Nprl3 is regulated by the Unassembled Soluble Complex Proteins Degradation (USPD) pathway. In addition, we demonstrated that the Nprl3 protein continually undergoes FK506 binding protein 39 (FKBP39)-dependent proteolytic destruction under nutrient replete conditions. However, nutrient starvation blocks 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. This work uncovered novel mechanisms of Nprl3 regulation and identified an important role for FKBP39 in the control of cellular metabolism.The multi-protein GATOR2 complex inhibits the activity of GATOR1 and thus promotes TORC1 activation. We have determined that Wdr59, originally assigned to the GATOR2 complex based on studies performed in tissue culture cells, unexpectedly has a dual function in TORC1 regulation in Drosophila. We find that in the ovary and the eye imaginal disc brain complex, Wdr59 inhibits TORC1 activity by opposing the GATOR2 dependent inhibition of GATOR1. Conversely, in the Drosophila fat body, Wdr59 promotes the accumulation of the GATOR2 component Mio and is required for TORC1 activation. Taken together, our data support the model that the Wdr59 component of the GATOR2 complex functions to promote or inhibit TORC1 activity depending on cellular context.

TORC1的失调导致了各种各样的人类病理。在过去的一年中，我们定义了几种控制多蛋白TORC1抑制剂间隙活性对RAGS 1（GATOR1）的成分的丰度（Gator1）。 Gator1复合物由三种蛋白质NPRL2，NPRL3和IML1组成。我们确定在果蝇中，NPRL3的稳定性受未组装的可溶性复合蛋白降解（USPD）途径的调节。此外，我们证明了NPRL3蛋白不断经历FK506结合蛋白39（FKBP39）依赖性蛋白水解破坏，在营养成分条件下。然而，营养饥饿会阻止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中的突变降低了Torc1活性并增加自噬。这项工作发现了NPRL3调节的新型机制，并确定了FKBP39在控制细胞代谢中的重要作用。多蛋白Gator2复合物抑制了Gator1的活性，从而促进了Torc1激活。我们已经确定，最初基于在组织培养细胞中进行的研究分配给Gator2复合物的WDR59意外地在果蝇中的TORC1调节中具有双重功能。我们发现，在卵巢和眼睛想象的椎间盘脑复合物中，WDR59通过反对Gator2依赖的Gator1抑制TORC1活性。相反，在果蝇脂肪体中，WDR59促进了Gator2成分MIO的积累，并且是TORC1激活所必需的。综上所述，我们的数据支持了Gator2复合物的WDR59成分功能促进或抑制TORC1活性的模型，具体取决于细胞环境。

项目成果

The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster.

• DOI: 10.1534/g3.116.035337
• 发表时间: 2016-12-07
• 期刊: G3 (Bethesda, Md.)
• 作者: Wei Y;Reveal B;Cai W;Lilly MA
• 通讯作者: Lilly MA

The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function.

• DOI: 10.1371/journal.pgen.1006036
• 发表时间: 2016-05
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Cai W;Wei Y;Jarnik M;Reich J;Lilly MA
• 通讯作者: Lilly MA

FKBP39 controls nutrient dependent Nprl3 expression and TORC1 activity in Drosophila.

FKBP39 控制果蝇中营养依赖性 Nprl3 表达和 TORC1 活性

• DOI: 10.1038/s41419-021-03860-z
• 发表时间: 2021-06-02
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Zhou Y;Guo J;Wang X;Cheng Y;Guan J;Barman P;Sun MA;Fu Y;Wei W;Feng C;Lilly MA;Wei Y
• 通讯作者: Wei Y

DRP1-dependent mitochondrial fission initiates follicle cell differentiation during Drosophila oogenesis.

• DOI: 10.1083/jcb.201110058
• 发表时间: 2012-05-14
• 期刊: The Journal of cell biology
• 作者: Mitra K;Rikhy R;Lilly M;Lippincott-Schwartz J
• 通讯作者: Lippincott-Schwartz J

The TORC1 inhibitor Nprl2 protects age-related digestive function in Drosophila.

TORC1 抑制剂 Nprl2 可保护果蝇与年龄相关的消化功能。

• DOI: 10.18632/aging.102428
• 发表时间: 2019
• 期刊: Aging (Albany NY)
• 作者: Xi Junmeng;Cai Jiadong;Cheng Yang;Fu Yuanyuan;Wei Wanhong;Zhang Zhenbo;Zhuang Ziheng;Hao Yue;Lilly Mary A;Wei Youheng
• 通讯作者: Wei Youheng