Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0004671
UniProt IDP19525
Primary gene name(s)EIF2AK2
Synonym gene name(s)PKR, PRKR
Protein nameInterferon-induced, double-stranded RNA-activated protein kinase
Protein functionIFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus, HCV, hepatitis B virus, HBV, measles virus, MV and herpes simplex virus 1, HHV-1. Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2, EIF2S1, this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways, p38 MAP kinase, NF-kappa-B and insulin signaling pathways and transcription factors, JUN, STAT1, STAT3, IRF1, ATF3 involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway, ISP. Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1, IRS1 at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2, IRS2. Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin, GSN, sequestering the protein in an inactive conformation away from actin. {ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035}.
Subcellular locationCytoplasm. Nucleus. Cytoplasm, perinuclear region. Note=Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome, MDS, melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt-Jakob disease patients.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P19525
Gene Ontology
(Biological Process)
Complete annatation
activation of MAPKK activity [GO:0000186];
cellular response to amino acid starvation [GO:0034198];
defense response to virus [GO:0051607];
endoplasmic reticulum unfolded protein response [GO:0030968];
evasion or tolerance by virus of host immune response [GO:0030683];
innate immune response [GO:0045087];
negative regulation of apoptotic process [GO:0043066];
negative regulation of cell proliferation [GO:0008285];
negative regulation of osteoblast proliferation [GO:0033689];
negative regulation of translation [GO:0017148];
negative regulation of viral genome replication [GO:0045071];
positive regulation of chemokine production [GO:0032722];
positive regulation of cytokine production [GO:0001819];
positive regulation of NF-kappaB transcription factor activity [GO:0051092];
positive regulation of NIK/NF-kappaB signaling [GO:1901224];
positive regulation of stress-activated MAPK cascade [GO:0032874];
protein autophosphorylation [GO:0046777];
protein phosphorylation [GO:0006468];
regulation of hematopoietic progenitor cell differentiation [GO:1901532];
regulation of hematopoietic stem cell differentiation [GO:1902036];
regulation of hematopoietic stem cell proliferation [GO:1902033];
regulation of NLRP3 inflammasome complex assembly [GO:1900225];
response to interferon-alpha [GO:0035455];
response to toxic substance [GO:0009636];
response to virus [GO:0009615];
transcription, DNA-templated [GO:0006351];
translation [GO:0006412]
Gene Ontology
(Molecular Function)
Complete annatation
ATP binding [GO:0005524];
double-stranded RNA binding [GO:0003725];
eukaryotic translation initiation factor 2alpha kinase activity [GO:0004694];
non-membrane spanning protein tyrosine kinase activity [GO:0004715];
poly(A RNA binding [GO:0044822];
protein kinase activity [GO:0004672];
protein phosphatase type 2A regulator activity [GO:0008601];
protein serine/threonine kinase activity [GO:0004674]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytosol [GO:0005829];
membrane [GO:0016020];
nucleus [GO:0005634];
perinuclear region of cytoplasm [GO:0048471];
ribosome [GO:0005840]
Protein-protein interaction111596
Phylogenetic treeP19525
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: 9.022304641; Folds changes 16h: 6.836396152; Tested: untested;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: numerous RNA and DNA viruses
      Viral life cycle: translation
      Mechanism related to antiviral activity: targets EIF2A
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. CD30.3113658517526910.3569820049727190.478388261665228
AZA vs. DISU0.2277593851107990.374010879040580.89822839898246
AZA vs. IL70.330439098187590.08725845563298370.805019294883334
AZA vs. SAHA0.2758993037303190.2593345053903870.631944444593388
DISU vs. CD3-0.09507201803428190.8012502026408930.863766398813475
DISU vs. IL70.09416625253918840.711992076152780.926158744367761
DISU vs. SAHA0.04817798481661890.8706298160660910.966103245960785
DMSO vs. AZA-0.06343989818042580.7066819247742941
DMSO vs. CD3-0.3838091760827620.2433069250402160.348265693463674
DMSO vs. DISU-0.2923374914584970.2363722816886760.75357103555074
DMSO vs. IL70.4008551650841080.02661666934054750.332157525090028
DMSO vs. SAHA0.3308651131381420.1618349483131740.486766853619269
HIV vs. Mock in Activation0.2520719247917860.7281579967512810.999983755607037
HIV vs. Mock in Latency-0.01632943514856790.9213425497311960.999834320637052
IL7 vs. CD30.0281175984314360.9352138828734450.959727590996149
SAHA vs. CD3-0.06100382113975510.8659432950157510.905721263993422
SAHA vs. IL7-0.05886948221804810.8096127687671080.917639230811527
(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
1.9 0.000311093 1.3 0.045818353 1.6 0.118315856
(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 1.61773 0.000305467
(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
unknown unknown

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
0.977 1.033 0.991 0.938 0.907
(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
204211_x_at 2.17 Yes upregulated in CD4+ cells
204211_x_at 1.87 Yes upregulated in CD8+ cells

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
1QU6 NMR - A=1-170.
2A19 X-ray 2.5Å B/C=258-538.
2A1A X-ray 2.8Å B=258-538.
3UIU X-ray 2.9Å A/B=254-551.

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

HIV Partner Interaction Type PubMed
Envelope surface glycoprotein gp120 interacts with 17928446
Nef interacts with 19651874
Tat activates 15907845
Tat upregulates 12539042
Tat phosphorylated by 15737233
Pr55(Gag) interacts with 22190034
Tat interacts with 1708818
capsid interacts with 19651874
Vpu inhibits 22647704
Tat inhibits 7491766
Vif regulated by 23376165
Nef regulated by 23376165
Tat enhanced by 10400814
Pr55(Gag) regulated by 23376165
Tat binds 7491766
Envelope surface glycoprotein gp120 activates 17928446
Envelope surface glycoprotein gp160; precursor regulated by 21464971
Tat downregulates 2180064

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)
hsa05203 Viral carcinogenesis - Homo sapiens (human)