Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability (PubMed:10504407, PubMed:10655230, PubMed:12176355, PubMed:12215525, PubMed:15213227, PubMed:16054071, PubMed:16176978, PubMed:16121183, PubMed:15774759, PubMed:16601681, PubMed:26102367). Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation (PubMed:10655230, PubMed:11106749, PubMed:12176355, PubMed:15213227, PubMed:16176978, PubMed:26102367). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion (PubMed:10655230, PubMed:11106749, PubMed:12176355, PubMed:15213227, PubMed:16176978, PubMed:26102367). Required for the translational induction of protein kinase PRKCH following amino acid starvation (PubMed:19797084). Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:16176978, PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory (PubMed:16121183). Plays a role in neurite outgrowth inhibition (PubMed:23447528). Plays a role in feeding behavior to maintain amino acid homeostasis; contributes to the innate aversion toward diets of imbalanced amino acid composition (PubMed:16054071, PubMed:15774759). Plays a proapoptotic role in response to glucose deprivation (PubMed:20660158). Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (PubMed:12176355). (Microbial infection) Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication. (Microbial infection) Plays a role in modulating the adaptive immune response to Yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] (Microbial infection) Kinase activity is enhanced by alphavirus genomic RNA sequences (PubMed:16601681). Kinase activity is stimulated upon binding to uncharged tRNAs (PubMed:16601681). Activated by serum starvation (in vitro) (PubMed:10504407). Homodimer; homodimerization is important for kinase activation by uncharged tRNAs (By similarity). Interacts with GCN1; this interaction stimulates EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation (PubMed:24333428). Interacts with DNAJC3; this interaction inhibits EIF2AK4/GCN2 kinase activity during endoplasmic reticulum (ER), hypothermic and amino acid-starving stress conditions (PubMed:25329545). Expressed in liver (PubMed:10504407). Expressed predominantly in the hippocampal CA1 region and the dentate gyrus, and to a lesser degree in CA3 (at protein level) (PubMed:16121183). Expressed in liver, lung, brain, kidney, skeletal muscle and testis (PubMed:10504407, PubMed:10655230). Expressed weakly in heart and spleen (PubMed:10655230). Expressed in the hippocampal CA1 and CA3 regions, the dentate gyrus and cerebellum (PubMed:16121183). Isoform 1 is widely expressed (PubMed:12215525). Isoform 1 is expressed in brain, liver, skeletal muscle and testis (PubMed:10655230). Isoform 3 is expressed in lung, brain, testis, prostate and choroid plexus (PubMed:12215525). Isoform 4 is expressed in muscle, lung, kidney, brain, testis and prostate (PubMed:10655230, PubMed:12215525). The histidyl-tRNA synthetase-like region and protein kinase domains are necessary for eIF-2-alpha kinase activity and eIF-2-alpha-mediated translational control (PubMed:10655230). The histidyl-tRNA synthetase-like domain is necessary for binding to uncharged tRNAs (PubMed:16601681). Kinase domain 1 is a degenerate kinase domain (PubMed:10504407). Autophosphorylated; autophosphorylation on Thr-898 is increased upon amino acid starvation and in UV irradiation cells and inhibited in presence of IMPACT (PubMed:10504407, PubMed:10655230, PubMed:11106749, PubMed:12176355, PubMed:16601681, PubMed:24333428). Mice are viable, fertile, and exhibit no phenotypic abnormalities under standard growth conditions (PubMed:12215525). Show an increase in prenatal and neonatal mortalities when essential amino acids are absent in the maternal diet during gestation (PubMed:12215525, PubMed:15213227). In response to nutrient deprivation, display reduced abilities to chronically down-regulate hepatic protein synthesis, resulting in preservation of liver mass relative to body size and enhanced skeletal muscle loss (PubMed:15213227). Mice exhibit a lowered threshold for the induction of strong and robust long-term potentiation (LTP) in the CA1 neurons of the hippocampus and the consolidation of long-term memory (PubMed:16121183). Knockout and conditional knockout in the brain result in a diminution of the rate of food consumption and an impairment in the food aversion response in mice fed an imbalanced amino acid diet (PubMed:16054071). Mice are more susceptible to intranasal Sindbis virus infection, with high virus titers in the brain compared to similarly infected control animals (PubMed:16601681). Mice infected with yellow fever virus show a decrease in dendritic cell autophagy and an impairment in their capacity to present antigens to T-cells under amino acid starvation (PubMed:24310610). Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.