Multi-omics analysis of glucose-mediated signaling by a moonlighting Gβ protein Asc1/RACK1.
Multi-omics analysis of glucose-mediated signaling by a moonlighting Gβ protein Asc1/RACK1.
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DOI：
10.1371/journal.pgen.1009640
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发表时间：
2021-07
期刊：
影响因子：
4.5
通讯作者：
Dohlman HG
中科院分区：
文献类型：
--
作者：
Li S;Li Y;Rushing BR;Harris SE;McRitchie SL;Jones JC;Dominguez D;Sumner SJ;Dohlman HG
异源三聚体G蛋白最初是通过努力了解激素（如胰高血糖素和肾上腺素）对葡萄糖代谢的影响而发现的。另一方面，许多细胞代谢物，包括葡萄糖，作为G蛋白偶联受体的配体。在这里，我们研究了葡萄糖介导的受体信号传导的后果，特别是Gα亚基Gpa 2和非经典Gβ亚基的作用，在酵母中称为Asc 1，在动物中称为RACK 1。Asc 1/RACK 1特别令人感兴趣，因为它在细胞中具有多种看似无关的功能。这种“兼职”操作的存在使从基因型确定表型变得复杂。通过对单个基因缺失突变体的比较分析，并通过整合转录组学和代谢组学测量，我们确定了Gα和Gβ蛋白亚基对酵母中葡萄糖启动过程的相对贡献。我们确定Gpa 2主要参与调节碳水化合物代谢，而Asc 1主要参与氨基酸代谢。这两种蛋白质都参与调节嘌呤代谢。在这两个亚基中，Gpa 2调节更多数量的基因转录物，并且在确定对葡萄糖添加的响应幅度方面特别重要。我们的结论是，两个G蛋白亚基调节不同的，但互补的葡萄糖敏感受体下游的过程，以及最终导致细胞生长和代谢的变化的过程。尽管酵母中葡萄糖发酵的社会重要性，但这些细胞检测和响应葡萄糖的机制仍然不清楚。葡萄糖检测需要细胞表面受体与G蛋白偶联，G蛋白由两个亚基组成，而不是更典型的异源三聚体：α亚基Gpa 2和β亚基Asc 1（或人类RACK 1）。Asc 1/RACK 1也作为核糖体的亚基，在那里它调节参与葡萄糖发酵的蛋白质的合成。这份手稿使用全球代谢组学和转录组学来证明每个G蛋白亚基在传递葡萄糖信号中的不同作用。Gpa 2主要参与碳水化合物的代谢，而Asc 1/RACK 1有助于蛋白质合成和细胞分裂所必需的氨基酸的产生。这些发现揭示了葡萄糖信号传导的初始步骤和G蛋白亚基的几个独特和互补的功能。更广泛地说，这里使用的综合方法可能会指导确定人类复杂G蛋白和代谢信号网络拓扑结构的努力。
Heterotrimeric G proteins were originally discovered through efforts to understand the effects of hormones, such as glucagon and epinephrine, on glucose metabolism. On the other hand, many cellular metabolites, including glucose, serve as ligands for G protein-coupled receptors. Here we investigate the consequences of glucose-mediated receptor signaling, and in particular the role of a Gα subunit Gpa2 and a non-canonical Gβ subunit, known as Asc1 in yeast and RACK1 in animals. Asc1/RACK1 is of particular interest because it has multiple, seemingly unrelated, functions in the cell. The existence of such “moonlighting” operations has complicated the determination of phenotype from genotype. Through a comparative analysis of individual gene deletion mutants, and by integrating transcriptomics and metabolomics measurements, we have determined the relative contributions of the Gα and Gβ protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Of the two subunits, Gpa2 regulates a greater number of gene transcripts and was particularly important in determining the amplitude of response to glucose addition. We conclude that the two G protein subunits regulate distinct but complementary processes downstream of the glucose-sensing receptor, as well as processes that lead ultimately to changes in cell growth and metabolism. Despite the societal importance of glucose fermentation in yeast, the mechanisms by which these cells detect and respond to glucose have remained obscure. Glucose detection requires a cell surface receptor coupled to a G protein that is comprised of two subunits, rather than the more typical heterotrimer: an α subunit Gpa2 and the β subunit Asc1 (or RACK1 in humans). Asc1/RACK1 also serves as a subunit of the ribosome, where it regulates the synthesis of proteins involved in glucose fermentation. This manuscript uses global metabolomics and transcriptomics to demonstrate the distinct roles of each G protein subunit in transmitting the glucose signal. Whereas Gpa2 is primarily involved in the metabolism of carbohydrates, Asc1/RACK1 contributes to production of amino acids necessary for protein synthesis and cell division. These findings reveal the initial steps of glucose signaling and several unique and complementary functions of the G protein subunits. More broadly, the integrated approach used here is likely to guide efforts to determine the topology of complex G protein and metabolic signaling networks in humans.
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DOI：
10.1073/pnas.92.7.2984
发表时间：
1995-03-28
影响因子：
11.1
作者：
BHATTACHARYA, S;CHEN, L;POWERS, S
通讯作者：
POWERS, S
DOI：
10.1073/pnas.82.15.5060
发表时间：
1985-01-01
影响因子：
11.1
作者：
CASPERSON, GF;WALKER, N;BOURNE, HR
通讯作者：
BOURNE, HR
影响因子：
5.3
作者：
FIELD, J;NIKAWA, J;WIGLER, M
通讯作者：
WIGLER, M
影响因子：
2.9
作者：
Heenan, Erin J.;Vanhooke, Janeen L.;Dohlman, Henrik G.
通讯作者：
Dohlman, Henrik G.
影响因子：
2.9
作者：
Lien EC;Nagiec MJ;Dohlman HG
通讯作者：
Dohlman HG