Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0000176
UniProt IDP18848
Primary gene name(s)ATF4
Synonym gene name(s)CREB2, TXREB
Protein nameCyclic AMP-dependent transcription factor ATF-4
Protein functionTranscriptional activator. Binds the cAMP response element, CRE, consensus: 5'-GTGACGT[AC][AG]-3', a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production, By similarity. It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase, ASNS in response to endoplasmic reticulum, ER stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements, CRE in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. During ER stress response, activates the transcription of NLRP1, possibly in concert with other factors, PubMed:26086088. {ECO:0000250, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:26086088}.
Subcellular locationCytoplasm {ECO:0000250|UniProtKB:Q9ES19}. Cell membrane {ECO:0000250|UniProtKB:Q9ES19}. Nucleus {ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:22974638}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:20873783}. Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes, By similarity. Colocalizes with NEK6 at the centrosome, PubMed:20873783. {ECO:0000250|UniProtKB:Q9ES19, ECO:0000269|PubMed:20873783}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P18848
Gene Ontology
(Biological Process)
Complete annatation
cellular amino acid metabolic process [GO:0006520];
cellular response to amino acid starvation [GO:0034198];
cellular response to glucose starvation [GO:0042149];
cellular response to UV [GO:0034644];
circadian regulation of gene expression [GO:0032922];
gamma-aminobutyric acid signaling pathway [GO:0007214];
gluconeogenesis [GO:0006094];
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress [GO:0070059];
mRNA transcription from RNA polymerase II promoter [GO:0042789];
negative regulation of oxidative stress-induced neuron death [GO:1903204];
negative regulation of potassium ion transport [GO:0043267];
negative regulation of translational initiation in response to stress [GO:0032057];
PERK-mediated unfolded protein response [GO:0036499];
positive regulation of apoptotic process [GO:0043065];
positive regulation of gene expression [GO:0010628];
positive regulation of neuron apoptotic process [GO:0043525];
positive regulation of transcription, DNA-templated [GO:0045893];
positive regulation of transcription from RNA polymerase II promoter [GO:0045944];
positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance [GO:0061395];
positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress [GO:1990440];
positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress [GO:0036091];
positive regulation of transcription from RNA polymerase II promoter in response to stress [GO:0036003];
positive regulation of transcription from RNA polymerase I promoter [GO:0045943];
positive regulation of vascular endothelial growth factor production [GO:0010575];
regulation of transcription, DNA-templated [GO:0006355];
response to endoplasmic reticulum stress [GO:0034976];
response to manganese-induced endoplasmic reticulum stress [GO:1990737];
transcription from RNA polymerase II promoter [GO:0006366]
Gene Ontology
(Molecular Function)
Complete annatation
core promoter sequence-specific DNA binding [GO:0001046];
DNA binding [GO:0003677];
leucine zipper domain binding [GO:0043522];
protein heterodimerization activity [GO:0046982];
RNA polymerase II core promoter proximal region sequence-specific DNA binding [GO:0000978];
RNA polymerase II regulatory region sequence-specific DNA binding [GO:0000977];
RNA polymerase II transcription factor activity, sequence-specific DNA binding [GO:0000981];
RNA polymerase II transcription factor binding [GO:0001085];
sequence-specific DNA binding [GO:0043565];
transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding [GO:0001077];
transcription factor activity, RNA polymerase II transcription factor binding [GO:0001076];
transcription factor activity, sequence-specific DNA binding [GO:0003700];
transcription regulatory region DNA binding [GO:0044212]
Gene Ontology
(Cellular Component)
Complete annatation
ATF1-ATF4 transcription factor complex [GO:1990590];
ATF4-CREB1 transcription factor complex [GO:1990589];
CHOP-ATF4 complex [GO:1990617];
cytoplasm [GO:0005737];
dendrite membrane [GO:0032590];
Lewy body core [GO:1990037];
microtubule organizing center [GO:0005815];
neuron projection [GO:0043005];
nuclear periphery [GO:0034399];
nucleoplasm [GO:0005654];
nucleus [GO:0005634]
Protein-protein interaction106958
Phylogenetic treeP18848
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
      unknown
Brass et al., Science, 2008
      unknown
Smith et al., J. Immunol, 2010
      unknown
Interferon-stimulated
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. CD30.6877684293222630.03645725837560890.0766365130037904
AZA vs. DISU0.2517317534728980.3193482056739980.870594587976108
AZA vs. IL70.160164287201130.4034986025509470.999311006273513
AZA vs. SAHA-0.2382604805447810.3278978724706750.699707322993057
DISU vs. CD3-0.4498053414854940.2173092001795370.339382395721751
DISU vs. IL7-0.1004142331897740.6903069031255060.918641998995145
DISU vs. SAHA-0.4873139078182770.09464963502631970.392861352038006
DMSO vs. AZA-0.02261648391458960.8921810161645531
DMSO vs. CD3-0.7226503704634370.02447590302066360.052978373420445
DMSO vs. DISU-0.2761908892660920.2574550580073590.775349265421842
DMSO vs. IL70.1901713915400130.2888655579425050.776229640995234
DMSO vs. SAHA-0.2210252247612130.3476341705988450.698763718489224
HIV vs. Mock in Activation0.009823154268968250.987418966024060.999983755607037
HIV vs. Mock in Latency-0.05171031276490590.7529842446678920.999834320637052
IL7 vs. CD3-0.5208723235978250.1053307506141840.197419846307833
SAHA vs. CD3-0.949560307008440.007759004114075710.0207282737101792
SAHA vs. IL7-0.4013432881439410.0993010571050960.285988562247271
(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) FALSE
(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 0.474005 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
unknown unknown unknown unknown unknown
(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

Drugbank ID Drug Name Drug Status Pharmacological Action Drug Action
DB00852 Pseudoephedrine approved unknown unknown

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
1CI6 X-ray 2.6Å A=280-341.

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

HIV Partner Interaction Type PubMed
Tat enhanced by 22050711
Vpu stabilizes 14561767
Tat interacts with 22050711

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04010 MAPK signaling pathway - Homo sapiens (human)
hsa04022 cGMP-PKG signaling pathway - Homo sapiens (human)
hsa04141 Protein processing in endoplasmic reticulum - Homo sapiens (human)
hsa04151 PI3K-Akt signaling pathway - Homo sapiens (human)
hsa04210 Apoptosis - Homo sapiens (human)
hsa04211 Longevity regulating pathway - Homo sapiens (human)
hsa04261 Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
hsa04668 TNF signaling pathway - Homo sapiens (human)
hsa04720 Long-term potentiation - Homo sapiens (human)
hsa04722 Neurotrophin signaling pathway - Homo sapiens (human)
hsa04725 Cholinergic synapse - Homo sapiens (human)
hsa04728 Dopaminergic synapse - Homo sapiens (human)
hsa04911 Insulin secretion - Homo sapiens (human)
hsa04912 GnRH signaling pathway - Homo sapiens (human)
hsa04915 Estrogen signaling pathway - Homo sapiens (human)
hsa04918 Thyroid hormone synthesis - Homo sapiens (human)
hsa04922 Glucagon signaling pathway - Homo sapiens (human)
hsa04925 Aldosterone synthesis and secretion - Homo sapiens (human)
hsa04932 Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
hsa05030 Cocaine addiction - Homo sapiens (human)
hsa05031 Amphetamine addiction - Homo sapiens (human)
hsa05034 Alcoholism - Homo sapiens (human)
hsa05161 Hepatitis B - Homo sapiens (human)
hsa05166 HTLV-I infection - Homo sapiens (human)
hsa05203 Viral carcinogenesis - Homo sapiens (human)
hsa05215 Prostate cancer - Homo sapiens (human)
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