DDIT3
Description
The DDIT3 (DNA damage inducible transcript 3) is a protein-coding gene located on chromosome 12.
DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.
== Structure == C/EBP proteins are known to have a conserved C-terminal structure, basic leucine zipper domain(bZIP), that is necessary for the formation of DNA-binding capable homodimers or heterodimers with other proteins or members of the C/EBP protein family. CHOP is a relatively small (29kDa) protein that differs from most C/EBP proteins in several amino acid substitutions, which impacts its DNA-binding ability.
== Regulation and function == Due to a variety of upstream and downstream regulatory interactions, CHOP plays an important role in ER stress-induced apoptosis caused by a variety of stimuli such as pathogenic microbial or viral infections, amino acid starvation, mitochondrial stress, neurological diseases, and neoplastic diseases. Under normal physiological conditions, CHOP is ubiquitously present at very low levels. However, under overwhelming ER stress conditions, the expression of CHOP rises sharply along with the activation of apoptotic pathways in a wide variety of cells. Those processes are mainly regulated by three factors: protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring protein 1 (IRE1α)
=== Upstream regulatory pathways === During ER stress, CHOP is mainly induced via activation of the integrated stress response pathways through the subsequent downstream phosphorylation of a translation initiation factor, eukaryotic initiation factor 2α (eIF2α), and induction of a transcription factor, activation transcription factor 4 (ATF4), which converges on the promoters of target genes, including CHOP. Integrated stress response, and thus CHOP expression, can be induced by
amino acid starvation through general control non-derepressible-2 (GCN2) viral infection through the vertebrate-specific kinases - double-stranded RNA-activated protein kinase (PKR) iron deficiency through heme-regulated inhibitor kinase (HRI) stress from the accumulation of unfolded or misfolded proteins in the ER activates the integrated stress response through protein kinase RNA-like endoplasmic reticulum kinase (PERK).
DDIT3, also known as C/EBP homologous protein (CHOP), is a multifunctional transcription factor that plays a crucial role in the endoplasmic reticulum (ER) stress response. It acts as a central mediator of cellular responses to a wide range of stresses, including ER stress, amino acid starvation, viral infection, and oxidative stress. DDIT3 induces cell cycle arrest and apoptosis in response to ER stress. DDIT3 functions as a dual regulator, acting both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes. It acts as a dominant-negative regulator of C/EBP-induced transcription by dimerizing with C/EBP family members, disrupting their binding to promoter regions and inhibiting the expression of C/EBP-regulated genes. DDIT3 positively regulates the transcription of genes involved in ER stress response, including TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM, and ERO1L. It negatively regulates the expression of genes such as BCL2, MYOD1, and CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG). In collaboration with ATF4, DDIT3 mediates ER-mediated cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation, and the unfolded protein response (UPR) in response to ER stress. DDIT3 inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, disrupting its DNA-binding properties and suppressing its transcriptional activity. DDIT3 plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11), which activates caspase-1 (CASP1) leading to the maturation of IL1B, a key inflammatory cytokine. DDIT3 acts as a major regulator of postnatal neovascularization by influencing endothelial nitric oxide synthase (NOS3)-related signaling. DDIT3 forms heterodimers with other proteins, including TCF7L2/TCF4, EP300/P300, HDAC1, HDAC5, and HDAC6. It interacts with TRIB3, which blocks its association with EP300/P300. DDIT3 also interacts with FOXO3, CEBPB, and ATF4.
DDIT3 is also known as AltDDIT3, C/EBPzeta, CEBPZ, CHOP, CHOP-10, CHOP10, GADD153.
