TRANSLATIONAL REGULATION OFGCN4AND THE GENERAL AMINO ACID CONTROL OF YEAST

Abstract

Cells reprogram gene expression in response to environmental changes by mobilizing transcriptional activators. The activator protein Gcn4 of the yeast Saccharomyces cerevisiae is regulated by an intricate translational control mechanism, which is the primary focus of this review, and also by the modulation of its stability in response to nutrient availability. Translation of GCN4 mRNA is derepressed in amino acid-deprived cells, leading to transcriptional induction of nearly all genes encoding amino acid biosynthetic enzymes. The trans-acting proteins that control GCN4 translation have general functions in the initiation of protein synthesis, or regulate the activities of initiation factors, so that the molecular events that induce GCN4 translation also reduce the rate of general protein synthesis. This dual regulatory response enables cells to limit their consumption of amino acids while diverting resources into amino acid biosynthesis in nutrient-poor environments. Remarkably, mammalian cells use the same strategy to downregulate protein synthesis while inducing transcriptional activators of stress-response genes under various stressful conditions, including amino acid starvation.

Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi

“…Starvation for amino acids stimulates the expression of genes of the amino-acid (AA) biosynthetic pathways by 658 Growth and development: eukaryotes the general control non-derepressible (GCN) response (reviewed in [43]). This response depends on the bZIP transcription factor Gcn4.…”

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

“…In mammalian cells, phosphorylation of eIF2 is mediated by four diVerent protein kinases (PKR, HRI, GCN2 and PERK), which are activated in response to diVerent cellular stresses such as a viral infection, heme deWciency in erythrocytes, nutrient starvation and accumulation of unfolded proteins in the ER [reviewed in Holcik and Sonenberg (2005)]. Gcn2p, the only eIF2 kinase in yeast, is activated upon depletion of any amino acid by binding the corresponding uncharged tRNA at its regulatory C-terminal domain, which is related to the histidyl-tRNA synthetase (HisRS) (reviewed in Hinnebusch 2005). In addition to inhibiting translation initiation of almost all mRNAs, eIF2 -P activates the expression of Gcn4p by a unique translational control mechanism (reviewed in Hinnebusch 2005).…”

“…Gcn2p, the only eIF2 kinase in yeast, is activated upon depletion of any amino acid by binding the corresponding uncharged tRNA at its regulatory C-terminal domain, which is related to the histidyl-tRNA synthetase (HisRS) (reviewed in Hinnebusch 2005). In addition to inhibiting translation initiation of almost all mRNAs, eIF2 -P activates the expression of Gcn4p by a unique translational control mechanism (reviewed in Hinnebusch 2005). Gcn4p is the major transcriptional activator of amino acid biosynthetic genes that is activated under amino acid starvation (Natarajan et al 2001), a cellular response named general amino acid control (GAAC).…”

Global translational reprogramming is a fundamental layer of immune regulation in plants

“…In this study, we found that the inhibitory effects of uORFs and R-motif on PTI-associated genes are rapidly alleviated upon immune induction in Arabidopsis . In yeast, uORF inhibition on GCN4 translation is removed during amino acid starvation through GCN2-mediated phosphorylation of the translation initiation factor eIF2α 20 . Surprisingly, GCN2-mediated eIF2α phosphorylation is not required for elf18-induced TBF1 translation or resistance (Extended Data Fig.…”