Multi-omics analysis of glucose-mediated signaling by a moonlighting Gβ protein Asc1/RACK1

Autor: Blake R. Rushing, Susan Sumner, Shuang Li, Janice C. Jones, Daniel Dominguez, Yuanyuan Li, Henrik G. Dohlman, Sarah E. Harris, Susan McRitchie
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cancer Research
Cell Physiology
Saccharomyces cerevisiae Proteins
G protein
Protein subunit
Carbohydrates
Saccharomyces cerevisiae
Carbohydrate metabolism
Biology
QH426-470
Biosynthesis
Biochemistry
Receptors
G-Protein-Coupled
Glucose Metabolism
GTP-Binding Proteins
Heterotrimeric G protein
Genetics
Metabolomics
Receptor
Molecular Biology
Gene
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Adaptor Proteins
Signal Transducing
Organic Compounds
Gene Expression Profiling
Monosaccharides
Organic Chemistry
Chemical Compounds
Biology and Life Sciences
Metabolism
Cell Biology
GTP-Binding Protein alpha Subunits
Cell biology
Cell Metabolism
Amino Acid Metabolism
Metabolic pathway
Chemistry
Glucose
Purines
Physical Sciences
Mutation
Purine Metabolism
Carbohydrate Metabolism
Metabolic Pathways
Research Article
Signal Transduction
Zdroj: PLoS Genetics, Vol 17, Iss 7, p e1009640 (2021)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary 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.
Databáze: OpenAIRE
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