Cell Cycle Regulation In Oogenesis

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

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.