Abstract
TORC1 is a central regulator of cell growth in response to amino acids. The role of the evolutionarily conserved Gtr/Rag pathway in the regulation of TORC1 is well-established. Recent genetic studies suggest that an additional regulatory pathway, depending on the activity of Pib2, plays a role in TORC1 activation independently of the Gtr/Rag pathway. However, the interplay between the Pib2 pathway and the Gtr/Rag pathway remains unclear. In this study, we show that Pib2 and Gtr/Ego form distinct complexes with TORC1 in a mutually exclusive manner, implying dedicated functional relationships between TORC1 and Pib2 or Gtr/Rag in response to specific amino acids. Furthermore, simultaneous depletion of Pib2 and the Gtr/Ego system abolishes TORC1 activity and completely compromises the vacuolar localization of TORC1. Thus, the amino acid-dependent activation of TORC1 is achieved through the Pib2 and Gtr/Ego pathways alone. Finally, we show that glutamine induces a dose-dependent increase in Pib2-TORC1 complex formation, and that glutamine binds directly to the Pib2 complex. These data provide strong preliminary evidence for Pib2 functioning as a putative glutamine sensor in the regulation of TORC1.
Highlights
Cell growth is primarily governed by environmental nutritional conditions [1]
We show that the amino acid-dependent activation of TORC1 is achieved through the Pib2 and Gtr/Ego pathways by anchoring them to the vacuolar membrane
Recent work has demonstrated that Gtr2 is regulated by its own GTPase-activating protein (GAP), Lst4–Lst7, which is an orthologue of mammalian FNIP–Folliculin and appears to be controlled by amino acid availability [16,17,18], suggesting that a similar system may exist for Gtr1
Summary
Cell growth is primarily governed by environmental nutritional conditions [1]. TORC1, a protein complex that is universally conserved among eukaryotes, plays a pivotal role in the cell’s coordinated response to amino acids [2,3]. The most well-established regulator of TORC1 is the heterodimeric small GTPase complex Gtr1–Gtr, the orthologue of which is RagA/B–RagC/D in mammals [8,9]. Multiple amino acid sensor proteins were identified in mammals, namely Sestrin and CASTOR, which are leucine and arginine sensor proteins, respectively [14,15] It remains unclear whether similar amino acid sensors exist in yeast. Recent work has demonstrated that Gtr is regulated by its own GTPase-activating protein (GAP), Lst4–Lst, which is an orthologue of mammalian FNIP–Folliculin and appears to be controlled by amino acid availability [16,17,18], suggesting that a similar system may exist for Gtr
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