The Vam6 GEF Controls TORC1 by Activating the EGO Complex
The Vam6 GEF Controls TORC1 by Activating the EGO Complex
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DOI：
10.1016/j.molcel.2009.06.033
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发表时间：
2009-09-11
期刊：
影响因子：
16
通讯作者：
De Virgilio, Claudio
中科院分区：
文献类型：
--
作者：
Binda, Matteo;Peli-Gulli, Marie-Pierre;De Virgilio, Claudio
雷帕霉素复合体1 （TORC1）的靶标是真核细胞生长的中心调节剂，可被多种激素（如胰岛素）和营养物质（如氨基酸）激活，在多种癌症中不受调节。在这里，我们报道了酵母Rag GTPase同源物Gtr1，液泡膜相关EGO复合体（EGOC）的一个组成部分，以氨基酸敏感的方式与TORC1相互作用并激活TORC1。GTP结合的组成活性Gtr1（GTP）的表达与TORC1强烈相互作用，使TORC1部分抵抗亮氨酸剥夺，而生长抑制Gtr1（GDP）的表达导致TORC1组成性低活性。我们还发现Gtr1的核苷酸结合状态受保守的鸟嘌呤核苷酸交换因子（GEF） Vam6的调控。因此，除了在HOPS复合体内的同型液泡融合和液泡蛋白分选中发挥调节作用外，Vam6还通过激活EGO复合体的Gtr1亚基来控制TORC1功能。
The target of rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is activated by a variety of hormones (e.g., insulin) and nutrients (e.g., amino acids) and is deregulated in various cancers. Here, we report that the yeast Rag GTPase homolog Gtr1, a component of the vacuolar-membrane-associated EGO complex (EGOC), interacts with and activates TORC1 in an amino-acid-sensitive manner. Expression of a constitutively active (GTP-bound) Gtr1(GTP), which interacted strongly with TORC1, rendered TORC1 partially resistant to leucine deprivation, whereas expression of a growth inhibitory, GDP-bound Gtr1(GDP), caused constitutively low TORC1 activity. We also show that the nucleotide-binding status of Gtr1 is regulated by the conserved guanine nucleotide exchange factor (GEF) Vam6. Thus, in addition to its regulatory role in homotypic vacuolar fusion and vacuole protein sorting within the HOPS complex, Vam6 also controls TORC1 function by activating the Gtr1 subunit of the EGO complex.