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

By Shuang Li, Yuanyuan Li, Blake R Rushing, Susan L McRitchie, Janice C Jones, Susan J Sumner, Henrik G Dohlman

Posted 13 Jan 2021
bioRxiv DOI: 10.1101/2021.01.12.426444

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 G subunit Gpa2 and a non-canonical G{beta} 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 G and G{beta} protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating sugar 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 leadultimately to changes in cell growth and metabolism.

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