DNA damage-inducible transcript 3

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.

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.

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)

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

Under ER stress, activated transmembrane protein ATF6 translocates to the nucleus and interacts with ATF/cAMP response elements and ER stress-response elements, binding the promoters and inducing transcription of several genes involved in unfolded protein response (including CHOP, XBP1 and others). Thus, ATF6 activates the transcription of both CHOP and XBP-1, while XBP-1 can also upregulate the expression of CHOP.

ER stress also stimulates transmembrane protein IRE1α activity. Upon activation, IRE1α splices the XBP-1 mRNA introns to produce a mature and active XBP-1 protein, that upregulates CHOP expression IRE1α also stimulates the activation of the apoptotic-signaling kinase-1 (ASK1), which then activates the downstream kinases, Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), which participate in apoptosis induction along with CHOP. The P38 MAP kinase family phosphorylates Ser78 and Ser81 of CHOP, which induces cell apoptosis. Moreover, research studies found that the JNK inhibitors can suppress CHOP upregulation, indicating that JNK activation is also involved in the modulation of CHOP levels.