PAS kinase is activated by direct SNF1-dependent phosphorylation and mediates inhibition of TORC1 through the phosphorylation and activation of Pbp1.
PAS kinase is activated by direct SNF1-dependent phosphorylation and mediates inhibition of TORC1 through the phosphorylation and activation of Pbp1.
复制标题
PAS激酶通过直接依赖SNF1的磷酸化激活，并通过PBP1的磷酸化和激活介导Torc1抑制。
DOI：
10.1091/mbc.e14-06-1088
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发表时间：
2015-02-01
影响因子：
3.3
通讯作者：
Grose JH
中科院分区：
文献类型：
--
作者：
DeMille D;Badal BD;Evans JB;Mathis AD;Anderson JF;Grose JH
当能量较低时，AMPK、Psk1和TORC1之间的相互作用会减少细胞的生长和增殖。这种相互作用是通过依赖于Snf1的Psk1激活，然后是聚(A)结合蛋白结合蛋白1(Pbp1)的磷酸化，以及随后TORC1对应激颗粒的抑制作用而发生的。我们描述了酵母中三种感觉蛋白激酶之间的相互作用：AMPK(酵母中为SNF1)、PAS激酶1(酵母中为Psk1)和雷帕霉素复合体1的靶标(TORC1)。这一信号级联通过SNF1依赖的Psk1的磷酸化和激活而发生，Psk1磷酸化并激活Poly(A)结合蛋白结合蛋白1(Pbp1)，然后Pbp1通过隔离在应激颗粒上抑制TORC1。依赖SNF1的Psk1的磷酸化似乎是直接的，因为Snf1是Psk1被替代碳源激活的必要条件和充分条件，是改变Psk1蛋白迁移率所必需的，能够在体外磷酸化Psk1，并通过其底物靶向亚基Gal83结合Psk1。Psk1直接磷酸化和激活Pbp1的证据也被体外和体内的激酶检测所提供，包括Pas激酶缺乏的酵母中Pbp1在不同细胞质部位的定位减少和随后TORC1抑制的挽救。为了支持这一信号级联反应，Snf1缺乏的细胞表现出TORC1活性的增加，而含有高活性Snf1的细胞表现出PAS激酶依赖的TORC1活性的降低。酵母SNF1、Psk1和TORC1之间的这种相互作用允许在营养耗竭期间适当地分配葡萄糖，在低能量时减少细胞的生长和增殖。
The interplay between AMPK, Psk1, and TORC1 reduces cell growth and proliferation when energy is low. This interplay occurs through Snf1-dependent activation of Psk1, followed by phosphorylation of poly(A)-binding protein binding protein 1 (Pbp1) and subsequent inhibitory sequestration of TORC1 to stress granules. We describe the interplay between three sensory protein kinases in yeast: AMP-regulated kinase (AMPK, or SNF1 in yeast), PAS kinase 1 (Psk1 in yeast), and the target of rapamycin complex 1 (TORC1). This signaling cascade occurs through the SNF1-dependent phosphorylation and activation of Psk1, which phosphorylates and activates poly(A)- binding protein binding protein 1 (Pbp1), which then inhibits TORC1 through sequestration at stress granules. The SNF1-dependent phosphorylation of Psk1 appears to be direct, in that Snf1 is necessary and sufficient for Psk1 activation by alternate carbon sources, is required for altered Psk1 protein mobility, is able to phosphorylate Psk1 in vitro, and binds Psk1 via its substrate-targeting subunit Gal83. Evidence for the direct phosphorylation and activation of Pbp1 by Psk1 is also provided by in vitro and in vivo kinase assays, including the reduction of Pbp1 localization at distinct cytoplasmic foci and subsequent rescue of TORC1 inhibition in PAS kinase–deficient yeast. In support of this signaling cascade, Snf1-deficient cells display increased TORC1 activity, whereas cells containing hyperactive Snf1 display a PAS kinase–dependent decrease in TORC1 activity. This interplay between yeast SNF1, Psk1, and TORC1 allows for proper glucose allocation during nutrient depletion, reducing cell growth and proliferation when energy is low.