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 made several contributions to the understanding of how TOR complex I (TORC1) activity is regulated by two inhibitory multiprotein complexes. Tuberous sclerosis complex (TSC) is a potent inhibitor of TORC1. Over the last year, we demonstrated that the Rag GTPase acts in both the amino-acid-sensing and growth factor signaling pathways to control TORC1 activity through the regulation of TSC dynamics in HeLa cells and Drosophila. We found that TSC lysosomal-cytosolic exchange increases in response to both amino acid and growth factor restriction. Moreover, the rate of exchange mirrors TSC function, with depletions of the Rag GTPase blocking TSC lysosomal mobility and rescuing TORC1 activity. Finally, we demonstrated that the GATOR2 complex controls the phosphorylation of TSC2, which is essential for TSC exchange. Our data support the model that the amino acid and growth factor signaling pathways converge on the Rag GTPase to inhibit TORC1 activity through the regulation of TSC dynamics. Additionally, 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.