ATF4_RAT
ID ATF4_RAT Reviewed; 347 AA.
AC Q9ES19;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=Cyclic AMP-dependent transcription factor ATF-4;
DE Short=cAMP-dependent transcription factor ATF-4;
DE AltName: Full=Activating transcription factor 4 {ECO:0000303|PubMed:10924501};
DE Short=rATF-4 {ECO:0000303|PubMed:10924501};
GN Name=Atf4 {ECO:0000303|PubMed:10924501, ECO:0000312|RGD:621863};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH GABBR1 AND GABBR2, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=Brain;
RX PubMed=10924501; DOI=10.1074/jbc.m002727200;
RA Nehring R.B., Horikawa H.P.M., El Far O., Kneussel M., Brandstatter J.H.,
RA Stamm S., Wischmeyer E., Betz H., Karschin A.;
RT "The metabotropic GABAB receptor directly interacts with the activating
RT transcription factor 4.";
RL J. Biol. Chem. 275:35185-35191(2000).
RN [2]
RP TISSUE SPECIFICITY.
RX PubMed=8506317; DOI=10.1073/pnas.90.10.4679;
RA Vallejo M., Ron D., Miller C.P., Habener J.F.;
RT "C/ATF, a member of the activating transcription factor family of DNA-
RT binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs
RT their binding to cAMP response elements.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:4679-4683(1993).
CC -!- FUNCTION: Transcription factor that binds the cAMP response element
CC (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological
CC functions, as regulator of metabolic and redox processes under normal
CC cellular conditions, and as master transcription factor during
CC integrated stress response (ISR) (By similarity). Binds to asymmetric
CC CRE's as a heterodimer and to palindromic CRE's as a homodimer (By
CC similarity). Core effector of the ISR, which is required for adaptation
CC to various stress such as endoplasmic reticulum (ER) stress, amino acid
CC starvation, mitochondrial stress or oxidative stress. During ISR, ATF4
CC translation is induced via an alternative ribosome translation re-
CC initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation,
CC and stress-induced ATF4 acts as a master transcription factor of
CC stress-responsive genes in order to promote cell recovery (By
CC similarity). Promotes the transcription of genes linked to amino acid
CC sufficiency and resistance to oxidative stress to protect cells against
CC metabolic consequences of ER oxidation (By similarity). Activates the
CC transcription of NLRP1, possibly in concert with other factors in
CC response to ER stress. Activates the transcription of asparagine
CC synthetase (ASNS) in response to amino acid deprivation or ER stress.
CC However, when associated with DDIT3/CHOP, the transcriptional
CC activation of the ASNS gene is inhibited in response to amino acid
CC deprivation (By similarity). Together with DDIT3/CHOP, mediates
CC programmed cell death by promoting the expression of genes involved in
CC cellular amino acid metabolic processes, mRNA translation and the
CC terminal unfolded protein response (terminal UPR), a cellular response
CC that elicits programmed cell death when ER stress is prolonged and
CC unresolved (By similarity). Together with DDIT3/CHOP, activates the
CC transcription of the IRS-regulator TRIB3 and promotes ER stress-induced
CC neuronal cell death by regulating the expression of BBC3/PUMA in
CC response to ER stress. May cooperate with the UPR transcriptional
CC regulator QRICH1 to regulate ER protein homeostasis which is critical
CC for cell viability in response to ER stress (By similarity). In the
CC absence of stress, ATF4 translation is at low levels and it is required
CC for normal metabolic processes such as embryonic lens formation, fetal
CC liver hematopoiesis, bone development and synaptic plasticity (By
CC similarity). Acts as a regulator of osteoblast differentiation in
CC response to phosphorylation by RPS6KA3/RSK2: phosphorylation in
CC osteoblasts enhances transactivation activity and promotes expression
CC of osteoblast-specific genes and post-transcriptionally regulates the
CC synthesis of Type I collagen, the main constituent of the bone matrix
CC (By similarity). Cooperates with FOXO1 in osteoblasts to regulate
CC glucose homeostasis through suppression of beta-cell production and
CC decrease in insulin production. Activates transcription of SIRT4.
CC Regulates the circadian expression of the core clock component PER2 and
CC the serotonin transporter SLC6A4. Binds in a circadian time-dependent
CC manner to the cAMP response elements (CRE) in the SLC6A4 and PER2
CC promoters and periodically activates the transcription of these genes.
CC Mainly acts as a transcriptional activator in cellular stress
CC adaptation, but it can also act as a transcriptional repressor: acts as
CC a regulator of synaptic plasticity by repressing transcription, thereby
CC inhibiting induction and maintenance of long-term memory (By
CC similarity). Regulates synaptic functions via interaction with DISC1 in
CC neurons, which inhibits ATF4 transcription factor activity by
CC disrupting ATF4 dimerization and DNA-binding (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q06507}.
CC -!- SUBUNIT: Binds DNA as a homodimer and as a heterodimer. Heterodimer;
CC heterodimerizes with CEBPB. Heterodimer; heterodimerizes with
CC DDIT3/CHOP. Interacts with CEP290 (via an N-terminal region). Interacts
CC with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3 (By similarity). Interacts
CC (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-
CC termini) (PubMed:10924501). Forms a heterodimer with TXLNG in
CC osteoblasts (By similarity). Interacts (via its DNA binding domain)
CC with FOXO1 (C-terminal half); the interaction occurs in osteoblasts and
CC regulates glucose homeostasis through suppression of beta-cell
CC proliferation and a decrease in insulin production. Interacts with
CC SATB2; the interaction results in enhanced DNA binding and
CC transactivation by these transcription factors (By similarity).
CC Interacts with ABRAXAS2 (By similarity). Interacts with TRIB3,
CC inhibiting the transactivation activity of ATF4. Interacts with DISC1;
CC which inhibits ATF4 transcription factor activity by disrupting ATF4
CC dimerization and DNA-binding (By similarity). Interacts with
CC EP300/p300; EP300/p300 stabilizes ATF4 and increases its
CC transcriptional activity independently of its catalytic activity by
CC preventing its ubiquitination (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q06507,
CC ECO:0000269|PubMed:10924501}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:10924501}. Nucleus
CC speckle {ECO:0000250|UniProtKB:P18848}. Cytoplasm
CC {ECO:0000269|PubMed:10924501}. Cell membrane
CC {ECO:0000269|PubMed:10924501}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:P18848}.
CC Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes
CC (PubMed:10924501). Colocalizes with NEK6 at the centrosome. Recruited
CC to nuclear speckles following interaction with EP300/p300 (By
CC similarity). {ECO:0000250|UniProtKB:P18848,
CC ECO:0000269|PubMed:10924501}.
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, liver, spleen, lung and
CC muscle, but not testis. {ECO:0000269|PubMed:8506317}.
CC -!- DOMAIN: The BetaTrCP degron motif promotes binding to BTRC when
CC phosphorylated. {ECO:0000250|UniProtKB:P18848}.
CC -!- PTM: Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed
CC by proteasomal degradation and leading to down-regulate expression of
CC SIRT4. Interaction with EP300/p300 inhibits ubiquitination by
CC SCF(BTRC). {ECO:0000250|UniProtKB:P18848}.
CC -!- PTM: Phosphorylation at Ser-243 by RPS6KA3/RSK2 in osteoblasts enhances
CC transactivation activity and promotes osteoblast differentiation (By
CC similarity). Phosphorylated on the betaTrCP degron motif at Ser-217,
CC followed by phosphorylation at Thr-211, Ser-222, Ser-229, Ser-233 and
CC Ser-246, promoting interaction with BTRC and ubiquitination.
CC Phosphorylation is promoted by mTORC1 (By similarity). Phosphorylation
CC at Ser-213 by CK2 decreases its stability. Phosphorylated by NEK6 (By
CC similarity). {ECO:0000250|UniProtKB:P18848,
CC ECO:0000250|UniProtKB:Q06507}.
CC -!- PTM: Hydroxylated by PHD3, leading to decreased protein stability.
CC {ECO:0000250|UniProtKB:P18848}.
CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}.
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DR EMBL; AF252627; AAG31732.1; -; mRNA.
DR RefSeq; NP_077379.1; NM_024403.2.
DR AlphaFoldDB; Q9ES19; -.
DR SMR; Q9ES19; -.
DR BioGRID; 249453; 2.
DR IntAct; Q9ES19; 1.
DR STRING; 10116.ENSRNOP00000060302; -.
DR PhosphoSitePlus; Q9ES19; -.
DR PaxDb; Q9ES19; -.
DR ABCD; Q9ES19; 1 sequenced antibody.
DR DNASU; 79255; -.
DR Ensembl; ENSRNOT00000065304; ENSRNOP00000060302; ENSRNOG00000017801.
DR GeneID; 79255; -.
DR KEGG; rno:79255; -.
DR UCSC; RGD:621863; rat.
DR CTD; 468; -.
DR RGD; 621863; Atf4.
DR eggNOG; KOG4571; Eukaryota.
DR GeneTree; ENSGT00530000063801; -.
DR HOGENOM; CLU_055748_1_0_1; -.
DR InParanoid; Q9ES19; -.
DR OMA; WMTEKID; -.
DR OrthoDB; 1524842at2759; -.
DR PhylomeDB; Q9ES19; -.
DR PRO; PR:Q9ES19; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000017801; Expressed in pancreas and 20 other tissues.
DR ExpressionAtlas; Q9ES19; baseline and differential.
DR Genevisible; Q9ES19; RN.
DR GO; GO:1990590; C:ATF1-ATF4 transcription factor complex; ISO:RGD.
DR GO; GO:1990589; C:ATF4-CREB1 transcription factor complex; ISO:RGD.
DR GO; GO:0005813; C:centrosome; IEA:Ensembl.
DR GO; GO:1990617; C:CHOP-ATF4 complex; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0032590; C:dendrite membrane; IDA:RGD.
DR GO; GO:1990037; C:Lewy body core; ISO:RGD.
DR GO; GO:0043005; C:neuron projection; ISO:RGD.
DR GO; GO:0034399; C:nuclear periphery; ISO:RGD.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:RGD.
DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
DR GO; GO:0008140; F:cAMP response element binding protein binding; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:RGD.
DR GO; GO:0140296; F:general transcription initiation factor binding; IPI:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0043522; F:leucine zipper domain binding; ISO:RGD.
DR GO; GO:1990841; F:promoter-specific chromatin binding; ISO:RGD.
DR GO; GO:0008022; F:protein C-terminus binding; IPI:RGD.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0030282; P:bone mineralization; ISS:UniProtKB.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; ISO:RGD.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:1903351; P:cellular response to dopamine; ISO:RGD.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISO:RGD.
DR GO; GO:1990253; P:cellular response to leucine starvation; ISO:RGD.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEP:RGD.
DR GO; GO:0034644; P:cellular response to UV; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISO:RGD.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISS:UniProtKB.
DR GO; GO:0007214; P:gamma-aminobutyric acid signaling pathway; IDA:RGD.
DR GO; GO:0006094; P:gluconeogenesis; ISO:RGD.
DR GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; ISS:UniProtKB.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0070982; P:L-asparagine metabolic process; ISO:RGD.
DR GO; GO:0070309; P:lens fiber cell morphogenesis; ISS:UniProtKB.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:1903204; P:negative regulation of oxidative stress-induced neuron death; IMP:ParkinsonsUK-UCL.
DR GO; GO:0043267; P:negative regulation of potassium ion transport; IMP:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; ISS:UniProtKB.
DR GO; GO:0030182; P:neuron differentiation; IEP:RGD.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; ISS:UniProtKB.
DR GO; GO:0070169; P:positive regulation of biomineral tissue development; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:2000120; P:positive regulation of sodium-dependent phosphate transport; ISO:RGD.
DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:1990440; P:positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; ISO:RGD.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; ISO:RGD.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:RGD.
DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:1990737; P:response to manganese-induced endoplasmic reticulum stress; IEP:ParkinsonsUK-UCL.
DR GO; GO:0031667; P:response to nutrient levels; ISO:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEP:RGD.
DR InterPro; IPR029811; ATF4.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR046347; bZIP_sf.
DR PANTHER; PTHR13044:SF32; PTHR13044:SF32; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Biological rhythms; Cell membrane; Cytoplasm;
KW Cytoskeleton; DNA-binding; Hydroxylation; Isopeptide bond; Membrane;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..347
FT /note="Cyclic AMP-dependent transcription factor ATF-4"
FT /id="PRO_0000258022"
FT DOMAIN 274..337
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 202..296
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 276..296
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 301..337
FT /note="Interaction with GABBR1"
FT /evidence="ECO:0000269|PubMed:10924501"
FT REGION 302..330
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT MOTIF 213..222
FT /note="BetaTrCP degron motif"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT COMPBIAS 215..239
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 240..257
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 269..296
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 211
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 213
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT MOD_RES 217
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 222
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 229
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 233
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 234
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 246
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 307
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 256
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 268
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
SQ SEQUENCE 347 AA; 38152 MW; CCE6BD02F263296B CRC64;
MTEMSFLNSE VLAGDLMSPF DQSGLGAEES LGLLDDYLEV AKHFKPHGFS SDKAGSSEWL
AMDGLVSASD TGKEDAFSGT DWMLEKMDLK EFDFDALFRM DDLETMPDEL LATLDDTCDL
FAPLVQETNK EPPQTVNPIG HLPESVIKVD QAAPFTFLQP LPCSPGFLSS TPDHSFSLEL
GSEVDISEGD RKPDSAAYIT LTPQCVKEED TPSDSDSGIC MSPESYLGSP QHSPSTSRAP
PDSLPSPGVP RGSRPKPYDP PGVSVTAKVK TEKLDKKLKK MEQNKTAATR YRQKKRAEQE
ALTGECKELE KKNEALKEKA DSLAKEIQYL KDLIEEVRKA RGKKRVP
