Keeping the eIF2 alpha kinase Gcn2 in check

• Published in: Biochimica et biophysica acta Vol. 1843; no. 9; pp. 1948 - 1968
• Main Authors: Castilho, Beatriz A., Shanmugam, Renuka, Silva, Richard C., Ramesh, Rashmi, Himme, Benjamin M., Sattlegger, Evelyn
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2014; Elsevier
• Subjects: Amino Acid Sequence; Animals; eIF-2 Kinase - chemistry; eIF-2 Kinase - metabolism; eIF2; Gcn1; Gcn2; Humans; Models, Biological; Molecular Sequence Data; Ribosome; Ribosomes - metabolism; RNA, Transfer - metabolism; Signal Transduction; Translational regulation; Uncharged tRNA; Viral Proteins - metabolism; Gcn2; Ribosome; Translational regulation; Gcn1; Uncharged tRNA; eIF2
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2014.04.006

The protein kinase Gcn2 is present in virtually all eukaryotes and is of increasing interest due to its involvement in a large array of crucial biological processes. Some of these are universally conserved from yeast to humans, such as coping with nutrient starvation and oxidative stress. In mammals, Gcn2 is important for e.g. long-term memory formation, feeding behaviour and immune system regulation. Gcn2 has been also implicated in diseases such as cancer and Alzheimer's disease. Studies on Gcn2 have been conducted most extensively in Saccharomyces cerevisiae, where the mechanism of its activation by amino acid starvation has been revealed in most detail. Uncharged tRNAs stimulate Gcn2 which subsequently phosphorylates its substrate, eIF2α, leading to reduced global protein synthesis and simultaneously to increased translation of specific mRNAs, e.g. those coding for Gcn4 in yeast and ATF4 in mammals. Both proteins are transcription factors that regulate the expression of a myriad of genes, thereby enabling the cell to initiate a survival response to the initial activating cue. Given that Gcn2 participates in many diverse processes, Gcn2 itself must be tightly controlled. Indeed, Gcn2 is regulated by a vast network of proteins and RNAs, the list of which is still growing. Deciphering molecular mechanisms underlying Gcn2 regulation by effectors and inhibitors is fundamental for understanding how the cell keeps Gcn2 in check ensuring normal organismal function, and how Gcn2-associated diseases may develop or may be treated. This review provides a critical evaluation of the current knowledge on mechanisms controlling Gcn2 activation or activity.
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•Protein kinase Gcn2 is involved in a large array of crucial biological processes.•Gcn2 is also implicated in diseases and disorders.•Its multifaceted functions imply that Gcn2 activity must be tightly controlled.•Many proteins and RNAs regulate Gcn2 activation and activity.•Studies on Gcn2 regulation by other molecules are critically reviewed.