Keeping the eIF2 alpha kinase Gcn2 in check

Abstract

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.

Regulation of fetal liver growth in a model of diet restriction in the pregnant rat

“…Nonetheless, we consider eIF2␣ to be a candidate for the regulation of fetal liver protein synthesis under conditions of maternal nutrient deprivation. The primary eIF2␣ kinase, GCN2 (general control nonderepressible 2), is a Ser/Thr protein kinase that responds to amino acid deficiency through its ability to bind to uncharged tRNA (12). In recent years, the complex network of proteins by which cells regulate GCN2 activity has become apparent.…”

T cell metabolism drives immunity

“…IDO, which is often expressed at high levels by APCs or tumor cells, can deplete tryptophan within a tissue microenvironment, and this in turn can lead to inhibition of effector T cell proliferation and induction of anergy (Munn et al, 2002;Uyttenhove et al, 2003). Depletion of tryptophan causes activation of the integrated stress response inducer general control nonderepressible 2 (GCN2) kinase, which results in the inhibition of translation initiation and metabolic remodeling (Munn et al, 2005;Guo and Cavener, 2007;Castilho et al, 2014).…”

Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response

“…GCN1 is believed to be involved in the transfer of uncharged tRNAs from the ribosomal A site to the HisRS domain of GCN2, when both proteins are bound to translating ribosomes (Marton et al, 1997;Sattlegger and Hinnebusch, 2000). In mammals, GCN2 also regulates synaptic plasticity and memory formation, feeding behavior, cell cycle control, the sensing of intracellular bacterial invasion, and has been implicated in diseases such as cancer and Alzheimer's (reviewed in Castilho et al, 2014;Donnelly et al, 2013).…”

“…GCN2 is present in virtually all eukaryotes and is the only eIF2α kinase in S. cerevisiae, where it has been extensively studied (reviewed in Castilho et al, 2014;Hinnebusch, 2005).…”