Whi2 is a conserved negative regulator of TORC1 in response to low amino acids.
Whi2 is a conserved negative regulator of TORC1 in response to low amino acids.
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Whi2 是 TORC1 响应低氨基酸的保守负调节因子。
DOI：
10.1371/journal.pgen.1007592
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发表时间：
2018-08
期刊：
影响因子：
4.5
通讯作者：
Teng X
中科院分区：
文献类型：
--
作者：
Chen X;Wang G;Zhang Y;Dayhoff-Brannigan M;Diny NL;Zhao M;He G;Sing CN;Metz KA;Stolp ZD;Aouacheria A;Cheng WC;Hardwick JM;Teng X
酵母WHI 2最初是在细胞周期阻滞调节因子的遗传筛选中鉴定的，后来被认为在一般应激反应中起作用。然而，Whi 2的功能尚不清楚。Whi 2预测了与人类KCTD家族蛋白的结构和序列相似性，这些蛋白与几种癌症有关，并且与神经系统疾病有因果关系，但在很大程度上没有特征。这些酵母和人类蛋白质之间的保守功能的鉴定可以提供深入了解疾病机制。我们报告说，酵母WHI 2是一个新的负调节TORC 1需要抑制TORC 1活性和细胞生长，特别是在响应低氨基酸。与目前的观点相反，WHI 2在低葡萄糖下对TORC 1抑制作用不明显。唯一广泛保守的机制，积极抑制酵母和哺乳动物的TORC 1特异性响应于低氨基酸是保守的SEACIT/GATOR 1复合物，失活的TORC 1激活RAG-like GTP酶。出乎意料的是，Whi 2与这些已建立的GATOR 1样Npr 2-Npr 3-Iml 1和RAG样Gtr 1-Gtr 2复合物同时独立地起作用，并且也独立于PKA途径起作用。相反，Whi 2通过其结合伴侣蛋白磷酸酶Psr 1和Psr 2抑制TORC 1活性，这些蛋白磷酸酶以前被认为仅调节TORC 1下游的氨基酸水平。此外，抑制TORC 1的能力在含有SKP 1/BTB/POZ结构域的Whi 2样人蛋白KCTD 11中是保守的，但在测试的其他KCTD家族成员中不是。酵母和人体细胞对可用营养素水平下降做出反应，为更少的时间做好准备。营养感测的详细机制尚未得到很好的理解，但这些过程中的缺陷在癌症等疾病中起着关键作用。进化上保守的蛋白质复合物TORC 1是响应高营养素和低营养素的控制中心，特别是氨基酸。我们确定了酵母Whi 2和人类肿瘤抑制因子KCTD 11作为低氨基酸条件下TORC 1活性的新型抑制因子，并研究了Whi 2的详细机制。出乎意料的是，Whi 2的工作原理与TORC 1由SEACIT-Gtr复合物（哺乳动物GATOR 1-RAG复合物）控制的通常机制不同。此外，Whi 2和SEACIT-Gtr途径都独立地和平行地一起工作以抑制TORC 1。为了实现这一功能，Whi 2需要它的结合伴侣，酵母蛋白磷酸酶Psr 1和Psr 2，这两种酶以前被认为在氨基酸信号传导中在TORC 1的下游发挥作用。这些研究对人类KCTD 11具有重要意义，有助于促进对其病理作用的理解。
Yeast WHI2 was originally identified in a genetic screen for regulators of cell cycle arrest and later suggested to function in general stress responses. However, the function of Whi2 is unknown. Whi2 has predicted structure and sequence similarity to human KCTD family proteins, which have been implicated in several cancers and are causally associated with neurological disorders but are largely uncharacterized. The identification of conserved functions between these yeast and human proteins may provide insight into disease mechanisms. We report that yeast WHI2 is a new negative regulator of TORC1 required to suppress TORC1 activity and cell growth specifically in response to low amino acids. In contrast to current opinion, WHI2 is dispensable for TORC1 inhibition in low glucose. The only widely conserved mechanism that actively suppresses both yeast and mammalian TORC1 specifically in response to low amino acids is the conserved SEACIT/GATOR1 complex that inactivates the TORC1-activating RAG-like GTPases. Unexpectedly, Whi2 acts independently and simultaneously with these established GATOR1-like Npr2-Npr3-Iml1 and RAG-like Gtr1-Gtr2 complexes, and also acts independently of the PKA pathway. Instead, Whi2 inhibits TORC1 activity through its binding partners, protein phosphatases Psr1 and Psr2, which were previously thought to only regulate amino acid levels downstream of TORC1. Furthermore, the ability to suppress TORC1 is conserved in the SKP1/BTB/POZ domain-containing, Whi2-like human protein KCTD11 but not other KCTD family members tested. Yeast and human cells respond to declining levels of available nutrients to prepare ahead for leaner times. The detailed mechanisms of nutrient sensing are not well understood, but defects in these processes have key roles in diseases such as cancer. The evolutionarily conserved protein complex TORC1 is the control hub for responding to both high and low nutrients, particularly amino acids. We identified yeast Whi2 and the human tumor suppressor KCTD11 as novel suppressors of TORC1 activity in low amino acid conditions, and we investigated the detailed mechanisms for Whi2. Unexpectedly, Whi2 works differently from the usual mechanism where TORC1 is controlled by the SEACIT-Gtr complex (mammalian GATOR1-RAG complex). Furthermore, both the Whi2 and the SEACIT-Gtr pathways work independently and together in parallel to suppress TORC1. For this function, Whi2 requires its binding partners, the yeast protein phosphatases Psr1 and Psr2, which were previously thought to function downstream of TORC1 in amino acid signaling. These studies have important implications for human KCTD11 to help advance the understanding of its pathological role.
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