Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0004672
UniProt IDQ9P2K8
Primary gene name(s)EIF2AK4
Synonym gene name(s)GCN2, KIAA1338
Protein nameeIF-2-alpha kinase GCN2
Protein functionMetabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2, eIF-2-alpha/EIF2S1 on 'Ser-52' in response to low amino acid availability, PubMed:25329545. Plays a role as an activator of the integrated stress response, ISR required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. 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:26102367. Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. 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, By similarity. 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, By similarity. {ECO:0000250|UniProtKB:P15442, ECO:0000250|UniProtKB:Q9QZ05, ECO:0000269|PubMed:25329545, ECO:0000269|PubMed:26102367}.; FUNCTION:, 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, PubMed:24310610. {ECO:0000269|PubMed:24310610}.
Subcellular locationCytoplasm {ECO:0000250|UniProtKB:Q9QZ05}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: Q9P2K8
Gene Ontology
(Biological Process)
Complete annatation
adaptive immune response [GO:0002250];
cell cycle arrest [GO:0007050];
cellular response to amino acid starvation [GO:0034198];
cellular response to cold [GO:0070417];
cellular response to leucine starvation [GO:1990253];
cellular response to UV [GO:0034644];
defense response to virus [GO:0051607];
eiF2alpha phosphorylation in response to endoplasmic reticulum stress [GO:0036492];
induction by virus of host autophagy [GO:0039520];
learning [GO:0007612];
long-term memory [GO:0007616];
negative regulation by host of viral genome replication [GO:0044828];
negative regulation of CREB transcription factor activity [GO:0032792];
negative regulation of neuron differentiation [GO:0045665];
negative regulation of translational initiation [GO:0045947];
negative regulation of translational initiation in response to stress [GO:0032057];
neuron projection extension [GO:1990138];
positive regulation of adaptive immune response [GO:0002821];
positive regulation of defense response to virus by host [GO:0002230];
positive regulation of long-term synaptic potentiation [GO:1900273];
positive regulation of translational initiation in response to starvation [GO:0071264];
protein autophosphorylation [GO:0046777];
protein phosphorylation [GO:0006468];
regulation of eIF2 alpha phosphorylation by amino acid starvation [GO:0060733];
regulation of feeding behavior [GO:0060259];
regulation of translational initiation [GO:0006446];
regulation of translational initiation by eIF2 alpha phosphorylation [GO:0010998];
T cell activation involved in immune response [GO:0002286];
viral translation [GO:0019081]
Gene Ontology
(Molecular Function)
Complete annatation
ATP binding [GO:0005524];
eukaryotic translation initiation factor 2alpha kinase activity [GO:0004694];
protein serine/threonine kinase activity [GO:0004674];
tRNA binding [GO:0000049]
Gene Ontology
(Cellular Component)
Complete annatation
cytosolic ribosome [GO:0022626];
polysome [GO:0005844]
Protein-protein interaction136426
Phylogenetic treeQ9P2K8
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-0.03339444139113490.9201830954877320.94902145991454
AZA vs. DISU0.1350853266328020.5952785720687810.955158276076142
AZA vs. IL70.2222383378110140.2503192598318330.999311006273513
AZA vs. SAHA0.4933263878614280.04438012880162090.250562225064695
DISU vs. CD30.1558756212831170.6687678043252330.765975676802565
DISU vs. IL70.07832967929343370.7564204847044770.941786906610111
DISU vs. SAHA0.3595472817897020.2223254066853520.598797465729398
DMSO vs. AZA-0.02585310798071990.8782885059581451
DMSO vs. CD3-0.005581211108995980.9862763986247170.991146935868859
DMSO vs. DISU-0.1632457001952210.5052705017480540.910379656216314
DMSO vs. IL70.2555009327706670.1576181090068250.662233275718473
DMSO vs. SAHA0.5127776629389340.03076947007135470.187284836818958
HIV vs. Mock in Activation-0.0148556218196950.9809717116839960.999983755607037
HIV vs. Mock in Latency-0.01268723878727910.9391146730078940.999834320637052
IL7 vs. CD30.2638978086886580.4167129502934380.553597241298518
SAHA vs. CD30.5014423719421970.1689907372873980.264969779600077
SAHA vs. IL70.2674835356769650.275135994143520.52253999946068
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.12083 0.568137
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
-0.149 0.009

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
0.898 0.988 1.12 1.136 1.273
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

not found

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
retropepsin cleaves 23110064
integrase binds 23417324
HIV-1 virus replication inhibited by expression of human gene 23417324

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04141 Protein processing in endoplasmic reticulum - Homo sapiens (human)
hsa05160 Hepatitis C - Homo sapiens (human)
hsa05162 Measles - Homo sapiens (human)
hsa05164 Influenza A - Homo sapiens (human)
hsa05168 Herpes simplex infection - Homo sapiens (human)
hsa05169 Epstein-Barr virus infection - Homo sapiens (human)