{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P35638","secondaryAccessions":["F8VS99"],"uniProtkbId":"DDIT3_HUMAN","entryAudit":{"firstPublicDate":"1994-06-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1994-06-01","entryVersion":229,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"DNA damage-inducible transcript 3 protein"},"shortNames":[{"value":"DDIT-3"}]},"alternativeNames":[{"fullName":{"value":"C/EBP zeta"}},{"fullName":{"value":"C/EBP-homologous protein"},"shortNames":[{"value":"CHOP"}]},{"fullName":{"value":"C/EBP-homologous protein 10"},"shortNames":[{"value":"CHOP-10"}]},{"fullName":{"value":"CCAAT/enhancer-binding protein homologous protein"}},{"fullName":{"value":"Growth arrest and DNA damage-inducible protein GADD153"}}]},"genes":[{"geneName":{"value":"DDIT3"},"synonyms":[{"value":"CHOP"},{"value":"CHOP10"},{"value":"GADD153"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P35639"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15322075"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15775988"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16434966"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17709599"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18940792"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19672300"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20829347"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20876114"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22761832"}],"value":"Multifunctional transcription factor in endoplasmic reticulum (ER) stress response (PubMed:15322075, PubMed:15775988, PubMed:19672300). Plays an essential role in the response to a wide variety of cell stresses and induces cell cycle arrest and apoptosis in response to ER stress (PubMed:15322075, PubMed:15775988). Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes (By similarity). Acts as a dominant-negative regulator of C/EBP-induced transcription: dimerizes with members of the C/EBP family, impairs their association with C/EBP binding sites in the promoter regions, and inhibits the expression of C/EBP regulated genes (By similarity). Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L (PubMed:15775988, PubMed:17709599, PubMed:20876114, PubMed:22761832). Negatively regulates; expression of BCL2 and MYOD1, ATF4-dependent transcriptional activation of asparagine synthetase (ASNS), CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:18940792, PubMed:19672300, PubMed:20829347). Together with ATF4, mediates ER-mediated cell death by promoting expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the unfolded protein response (UPR) in response to ER stress (By similarity). Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity (PubMed:16434966). Plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11) which induces the activation of caspase-1 (CASP1) and both these caspases increase the activation of pro-IL1B to mature IL1B which is involved in the inflammatory response (By similarity). Acts as a major regulator of postnatal neovascularization through regulation of endothelial nitric oxide synthase (NOS3)-related signaling (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15775988"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16434966"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17872950"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18940792"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20829347"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22761832"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29083303"}],"value":"Heterodimer (PubMed:29083303). Interacts with TCF7L2/TCF4, EP300/P300, HDAC1, HDAC5 and HDAC6 (PubMed:16434966, PubMed:17872950). Interacts with TRIB3 which blocks its association with EP300/P300 (PubMed:15775988, PubMed:17872950). Interacts with FOXO3, CEBPB and ATF4 (PubMed:18940792, PubMed:20829347, PubMed:22761832)"}],"commentType":"SUBUNIT"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29083303"}],"value":"Interacts with isoform AltDDIT3 of DDIT3"}],"commentType":"SUBUNIT","molecule":"Isoform 1"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P15336","geneName":"ATF2","intActId":"EBI-1170906"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P18847","geneName":"ATF3","intActId":"EBI-712767"},"numberOfExperiments":38,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P18848","geneName":"ATF4","intActId":"EBI-492498"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P17544","geneName":"ATF7","intActId":"EBI-765623"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"O14867","geneName":"BACH1","intActId":"EBI-1263541"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q16520","geneName":"BATF","intActId":"EBI-749503"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q8N1L9","geneName":"BATF2","intActId":"EBI-742695"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q9NR55","geneName":"BATF3","intActId":"EBI-10312707"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P49715","geneName":"CEBPA","intActId":"EBI-1172054"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P17676","geneName":"CEBPB","intActId":"EBI-969696"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P49716","geneName":"CEBPD","intActId":"EBI-7962058"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q15744","geneName":"CEBPE","intActId":"EBI-3907048"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P53567","geneName":"CEBPG","intActId":"EBI-740209"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q9BSW2","geneName":"CRACR2A","intActId":"EBI-739773"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"O43889","geneName":"CREB3","intActId":"EBI-625002"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"O60519","geneName":"CREBL2","intActId":"EBI-2872455"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q10586","geneName":"DBP","intActId":"EBI-3908088"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P35638","geneName":"DDIT3","intActId":"EBI-742651"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q7Z589-5","geneName":"EMSY","intActId":"EBI-11989522"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P01100","geneName":"FOS","intActId":"EBI-852851"},"numberOfExperiments":11,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P15408","geneName":"FOSL2","intActId":"EBI-3893419"},"numberOfExperiments":6,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q13283","geneName":"G3BP1","intActId":"EBI-1047359"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P14136","geneName":"GFAP","intActId":"EBI-744302"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q16534","geneName":"HLF","intActId":"EBI-2798854"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q9BPX1","geneName":"HSD17B14","intActId":"EBI-742664"},"numberOfExperiments":6,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q8WYK2","geneName":"JDP2","intActId":"EBI-1248415"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q8WXH2","geneName":"JPH3","intActId":"EBI-1055254"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"P17275","geneName":"JUNB","intActId":"EBI-748062"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q8TBB1","geneName":"LNX1","intActId":"EBI-739832"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q9BTE3-2","geneName":"MCMBP","intActId":"EBI-9384556"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q16236","geneName":"NFE2L2","intActId":"EBI-2007911"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q16649","geneName":"NFIL3","intActId":"EBI-3951858"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q86SX3","geneName":"TEDC1","intActId":"EBI-3247115"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"O43508","geneName":"TNFSF12","intActId":"EBI-6932080"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q99757","geneName":"TXN2","intActId":"EBI-2932492"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"Q86VQ3","geneName":"TXNDC2","intActId":"EBI-1220595"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638","intActId":"EBI-742651"},"interactantTwo":{"uniProtKBAccession":"A5D8V6","geneName":"VPS37C","intActId":"EBI-2559305"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q9Y2J4-4","geneName":"AMOTL2","intActId":"EBI-10187270"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q8N5M1","geneName":"ATPAF2","intActId":"EBI-1166928"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q9NR55","geneName":"BATF3","intActId":"EBI-10312707"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"P53567","geneName":"CEBPG","intActId":"EBI-740209"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q494R4","geneName":"DRC12","intActId":"EBI-10241443"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q7Z589","geneName":"EMSY","intActId":"EBI-6598631"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"P15408","geneName":"FOSL2","intActId":"EBI-3893419"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q9BPX1","geneName":"HSD17B14","intActId":"EBI-742664"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"P25791","geneName":"LMO2","intActId":"EBI-739696"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"O75971","geneName":"SNAPC5","intActId":"EBI-749483"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q4ACW9","geneName":"TWEAK","intActId":"EBI-10241785"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"A5D8V6","geneName":"VPS37C","intActId":"EBI-2559305"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"P24278","geneName":"ZBTB25","intActId":"EBI-739899"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P35638-2","intActId":"EBI-10173632"},"interactantTwo":{"uniProtKBAccession":"Q6PJT7","geneName":"ZC3H14","intActId":"EBI-740660"},"numberOfExperiments":3,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29083303"}],"value":"Present in the cytoplasm under non-stressed conditions and ER stress leads to its nuclear accumulation"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29083303"}],"value":"Cytoplasm","id":"SL-0086"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29083303"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33384352"}],"value":"Nucleus","id":"SL-0191"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing","Alternative initiation"],"isoforms":[{"name":{"value":"1"},"isoformIds":["P35638-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["P35638-2"],"sequenceIds":["VSP_047277"],"isoformSequenceStatus":"Described"},{"name":{"value":"AltDDIT3"},"isoformIds":["P0DPQ6-1"],"isoformSequenceStatus":"External"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19855386"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20829347"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33384352"}],"value":"Up-regulated by oxidative stress, amino-acid deprivation, hypoxia and endoplasmic reticulum stress (PubMed:33384352). During ER stress, induced by a EIF2AK3/ATF4 pathway and/or ERN1/ATF6 pathway. Expression is suppressed by TLR-TRIF signaling pathway during prolonged ER stress"}],"commentType":"INDUCTION"},{"texts":[{"value":"The N-terminal region is necessary for its proteasomal degradation, transcriptional activity and interaction with EP300/P300"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17872950"}],"value":"Ubiquitinated, leading to its degradation by the proteasome"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Myxoid liposarcoma","diseaseAccession":"DI-03715","acronym":"MXLIPO","description":"A soft tissue tumor that tends to occur in the limbs (especially the thigh) of patients ranging in age from 35 to 55 years. It is defined by the presence of a hypocellular spindle cell proliferation set in a myxoid background, often with mucin pooling. Lipoblasts tend to be small and often monovacuolated and to cluster around vessels or at the periphery of the lesion.","diseaseCrossReference":{"database":"MIM","id":"613488"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7503811"}]},"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7503811"}],"value":"The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving DDIT3 has been found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with FUS (PubMed:7503811)"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the bZIP family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Miscellaneous discrepancy","sequence":"AAB27103.1","note":"Contaminating sequence. 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