ID:CREB3_HUMAN DESCRIPTION: RecName: Full=Cyclic AMP-responsive element-binding protein 3; Short=CREB-3; Short=cAMP-responsive element-binding protein 3; AltName: Full=Leucin zipper proitein; AltName: Full=Luman; AltName: Full=Transcription factor LZIP-alpha; Contains: RecName: Full=Processed cyclic AMP-responsive element-binding protein 3; Short=N-terminal Luman; Short=Transcriptionally active form; FUNCTION: Endoplasmic reticulum (ER)-bound transcription factor that plays a role in the unfolded protein response (UPR). Involved in cell proliferation and migration, tumor suppression and inflammatory gene expression. Plays also a role in the human immunodeficiency virus type 1 (HIV-1) virus protein expression and in the herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Isoform 2 plays a role in the unfolded protein response (UPR). Isoform 2 acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration. Isoform 2 may play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HSV) core protein. Isoform 2 represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestring host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection. Isoform 3 functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Isoform 3 decreases the acetylation level of histone H4. Isoform 3 does not promote the chemotactic activity of leukocyte cells. FUNCTION: Processed cyclic AMP-responsive element-binding protein 3: acts as a transcription factor that activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Promotes cell survival against ER stress-induced apoptotic cell death during UPR. Activates transcription from CRE and C/EBP-containing reporter genes. Induces transcriptional activation of chemokine receptors. Activates transcription of genes required for reactivation of the latent HSV-1 virus. Down- regulates Tat-dependent transcription of the HIV-1 LTR by interacting with HIV-1 Tat. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16 and by the HCV core protein. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]- 3') and C/EBP sequences present in many viral and cellular promoters. Binds to the unfolded protein respons element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3'). Associates with chromatin to the HERPUD1 promoter. SUBUNIT: Homodimer; homodimerization is prevented by the HCV core protein. Interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity. Isoform 2 interacts with CREBZF; the interaction occurs only in combination with HCFC1. Isoform 2 interacts (via central part and transmembrane region) with TM7SF4 (via C-terminus cytoplasmic domain). Isoform 2 interacts with OS9. Isoform 2 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation. Isoform 2 interacts (via C-terminal domain) with CCR1. Isoform 2 interacts (via leucine-zipper and transmembrane domains) with HIV- 1 ENV (via cytoplasmic domain). Isoform 2 interacts (via leucine- zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability. Interacts with the HCV core protein. Processed cyclic AMP- responsive element-binding protein 3 interacts with HIV-1 Tat. INTERACTION: P29846:- (xeno); NbExp=8; IntAct=EBI-625022, EBI-909718; P32246:CCR1; NbExp=7; IntAct=EBI-625022, EBI-608322; Q8IUR6:CREBRF; NbExp=4; IntAct=EBI-625022, EBI-1042699; Q9H295:DCSTAMP; NbExp=6; IntAct=EBI-625022, EBI-6095316; P51610:HCFC1; NbExp=5; IntAct=EBI-625002, EBI-396176; P05412:JUN; NbExp=4; IntAct=EBI-625002, EBI-852823; SUBCELLULAR LOCATION: Isoform 2: Endoplasmic reticulum membrane; Single-pass type II membrane protein. Membrane. Note=Colocalizes with HCFC1 in neuronal cell bodies of the trigeminal ganglia (By similarity). Colocalizes with TM7SF4 in the ER membrane of immature dendritic cell (DC). Colocalizes with CANX, CCR1, HCFC1 in the ER membrane. Sequestred into the cytoplasm by the HCV core protein. SUBCELLULAR LOCATION: Isoform 3: Nucleus. Cytoplasm. Note=Predominantly in the nucleus. SUBCELLULAR LOCATION: Processed cyclic AMP-responsive element- binding protein 3: Nucleus. Note=Upon RIP activation the transcriptional active processed cyclic AMP-responsive element- binding protein 3 form translocates into the nucleus. Detected in the nucleus upon dendritic cell maturation and RIP activation. Colocalizes with CREBRF in nuclear foci. Colocalizes with CREBZF in promyelocytic leukemia protein nuclear bodies (PML-NB). TISSUE SPECIFICITY: Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level). Ubiquitous. INDUCTION: Up-regulated upon differentiation of monocytes towards immature dendritic cells (DC). Down-regulated upon DC maturation. Up-regulated by endoplasmic reticulum stress triggered by thapsigargin (Tg) or tunicamycin (Tm). Up-regulated by CCR1- dependent chemokines in an immediate early response and biphasic manner and by NF-kappa-B. PTM: The ER membrane embedded cyclic AMP-responsive element- binding protein 3 form is first proteolytically cleaved by site-1 protease (S1P) that generates membrane-associated N-terminus and a luminal C-terminus forms. The membrane-associated N-terminus form is further proteolytically processed probably by the site-2 protease (S2P) through a regulated intramembrane proteolysis (RIP), releasing the transcriptional active processed cyclic AMP- responsive element-binding protein 3 form, which is transported to the nucleus. The proteolytic cleavage is strongly induced during dendritic cell (DC) maturation and inhibited by TM7SF4. PTM: The processed cyclic AMP-responsive element-binding protein 3 is rapidly degraded. PTM: N-glycosylated. SIMILARITY: Belongs to the bZIP family. ATF subfamily. SIMILARITY: Contains 1 bZIP (basic-leucine zipper) domain. CAUTION: All experiments concerning the proteolytic cleavage are done with isoform 2.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
SCOP Domains: 47454 - A DNA-binding domain in eukaryotic transcription factors 57959 - Leucine zipper domain
ModBase Predicted Comparative 3D Structure on O43889
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000977 RNA polymerase II regulatory region sequence-specific DNA binding GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0000982 transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0003677 DNA binding GO:0003682 chromatin binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0005515 protein binding GO:0008140 cAMP response element binding protein binding GO:0031726 CCR1 chemokine receptor binding GO:0035497 cAMP response element binding GO:0042803 protein homodimerization activity GO:0046983 protein dimerization activity
Biological Process: GO:0001558 regulation of cell growth GO:0002230 positive regulation of defense response to virus by host GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006935 chemotaxis GO:0006986 response to unfolded protein GO:0006990 positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response GO:0016032 viral process GO:0019043 establishment of viral latency GO:0019046 release from viral latency GO:0030335 positive regulation of cell migration GO:0030968 endoplasmic reticulum unfolded protein response GO:0034976 response to endoplasmic reticulum stress GO:0042127 regulation of cell proliferation GO:0042981 regulation of apoptotic process GO:0042994 cytoplasmic sequestering of transcription factor GO:0045786 negative regulation of cell cycle GO:0045893 positive regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0050930 induction of positive chemotaxis GO:0051928 positive regulation of calcium ion transport GO:0090026 positive regulation of monocyte chemotaxis GO:0090045 positive regulation of deacetylase activity GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway GO:2000326 negative regulation of ligand-dependent nuclear receptor transcription coactivator activity
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
