Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane.
Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane.
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DOI：
10.1371/journal.pgen.1007334
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发表时间：
2018-04
期刊：
影响因子：
4.5
通讯作者：
Noda T
中科院分区：
文献类型：
--
作者：
Ukai H;Araki Y;Kira S;Oikawa Y;May AI;Noda T
TORC1是细胞生长的中央调节因子，对氨基酸作出反应。进化上保守的GTR/RAG通路在调控TORC1中的作用是公认的。最近的遗传学研究表明，依赖于Pib2的活性，另一个额外的调节途径在TORC1的激活中发挥作用，而不是GTR/RAG途径。然而，Pib2通路和GTR/RAG通路之间的相互作用仍不清楚。在这项研究中，我们发现Pib2和GTR/EGO以一种互斥的方式与TORC1形成不同的复合体，这意味着TORC1与Pib2或Gtr/Rag之间存在特定的功能关系，以响应特定的氨基酸。此外，Pib2和GTR/EGO系统的同时耗尽会取消TORC1的活性，并完全破坏TORC1的空泡定位。因此，TORC1的氨基酸依赖性激活仅通过Pib2和Gtr/EGO途径实现。最后，我们证明了谷氨酰胺诱导Pib2-TORC1复合体形成的剂量依赖性增加，并且谷氨酰胺直接与Pib2复合体结合。这些数据为Pib2作为谷氨酰胺感受器在TORC1调控中的作用提供了强有力的初步证据。TORC1是细胞生长的中央调节因子，对氨基酸作出反应。在进化上保守的GTR/RAG通路是一条成熟的TORC1调节通路。在这项研究中，我们发现两个分子机制Pib2和Gtr/EGO以一种互斥的方式与TORC1形成不同的复合体，这意味着TORC1与Pib2或Gtr/Rag之间存在排他性的功能关系，以响应各种氨基酸。我们还表明，TORC1的氨基酸依赖的激活是通过Pib2和Gtr/EGO途径实现的，它们锚定在液泡膜上。最后，我们证明了谷氨酰胺直接与Pib2复合体结合，并促进了Pib2-TORC1复合体的形成。总而言之，我们提供了支持Pib2作为推测的谷氨酰胺传感器元件的作用的证据。
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. TORC1 is a central regulator of cell growth in response to amino acids. The evolutionarily conserved Gtr/Rag pathway is a well-established TORC1 regulatory pathway. In this study, we show that two molecular machineries, Pib2 and Gtr/Ego, form distinct complexes with TORC1 in a mutually exclusive manner, implying an exclusive functional relationship between TORC1 and Pib2 or Gtr/Rag in response to various amino acids. We also 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. Finally, we show that glutamine binds directly to the Pib2 complex and that glutamine enhances Pib2-TORC1 complex formation. Collectively we provide evidence supporting a role for Pib2 as an element of a putative glutamine sensor.
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