DNA damage-inducible transcript 3

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-

Regulation and function

Due to a variety of upstream and downstream regulatory interactions, CHOP plays an important role in

• amino acid starvation through general control non-derepressible-2 (GCN2)^[13]
• viral infection through the vertebrate-specific kinases - double-stranded RNA-activated protein kinase (PKR)^[14]
• iron deficiency through
  HRI)^[15]
• 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).^[16]

Under ER stress, activated transmembrane protein ATF6 translocates to the nucleus and interacts with ATF/cAMP response elements and ER stress-response elements,^[17] binding the promoters and inducing transcription of several genes involved in unfolded protein response (including CHOP, XBP1 and others).^[18][19] Thus, ATF6 activates the transcription of both CHOP and XBP-1, while XBP-1 can also upregulate the expression of CHOP.^[20]

ER stress also stimulates transmembrane protein IRE1α activity.^[21] Upon activation, IRE1α splices the XBP-1 mRNA introns to produce a mature and active XBP-1 protein,^[22] that upregulates CHOP expression^[23][24][25] 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),^[26] which participate in apoptosis induction along with CHOP.^[27] The P38 MAP kinase family phosphorylates Ser78 and Ser81 of CHOP, which induces cell apoptosis.^[28] 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.^[29]

Downstream pathways

Apoptosis induction via Mitochondria-Dependent Pathway

As a transcription factor, CHOP can regulate the expression of many anti-apoptotic and

TRB3 pseudokinase is upregulated by the ER stress-inducible transcriptional factor, ATF4-CHOP.^[38] CHOP interacts with TRB3, which contributes to the induction of apoptosis.^[39][40][41] The expression of TRB3 has a pro-apoptotic capacity.^[42][43] Therefore, CHOP also regulates apoptosis by upregulating the expression of the TRB3 gene.

Apoptosis induction via Death-Receptor Pathway

The PERK-ATF4-CHOP pathway can induce

Under prolonged ER stress conditions, activation of the PERK-CHOP pathway will permit DR5 protein levels to rise, which accelerates the formation of the death-inducing signaling complex (DISC) and activates caspase-8,^[46] leading to apoptosis^[47]

Apoptosis induction through other downstream pathways

In addition, CHOP also mediates apoptosis through increasing the expression of the ERO1α (ER reductase)^[10] gene, which catalyzes the production of H₂O₂ in the ER. The highly oxidized state of the ER results in H₂O₂ leakage into the cytoplasm, inducing the production of reactive oxygen species (ROS) and a series of apoptotic and inflammatory reactions.^{[10][48][49][50]}

The

Chop gene deletion has been demonstrated protective against diet induced metabolic syndromes in mice.^[60][61] Mice with germline Chop gene knockout have better glycemic control despite unchanged obesity. A plausible explanation for the observed dissociation between obesity and insulin resistance is that CHOP promotes insulin hypersecretion from pancreatic β cells.^[62]

Furthermore, Chop depletion by a GLP1-ASO delievery system^[63] was shown to have therapeutic effects of insulin reduction and fatty liver correction,^[64] in preclinical mouse models.^[62]

Role in microbial infection

CHOP-induced apoptosis pathways had been identified in cells infected by

• Porcine circovirus type 2 (PERK-eIF2α-ATF4 -CHOP-BCL2 pathway)^[65]
• HIV (XBP-1-CHOP-Caspase 3/9 pathway)^[66][67]
• Infectious bronchitis virus (PERK-eIF2α-ATF4/PKR-eIF2α-ATF4 pathway)^[68]
• M. tuberculosis (PERK-eIF2α-CHOP pathway)^[69][70]
• Helicobacter pylori (PERK-CHOP or PKR-eIF2α-ATF4 pathway)^[71]
• Escherichia coli (CHOP-DR5-Caspase 3/8 pathway)^[72]
• Shigella dysenteriae (p38-CHOP-DR5 pathway)^[73]

Since CHOP has an important role of apoptosis induction during infection, it is an important target for further research that will help deepen the current understanding of pathogenesis and potentially provide an opportunity for invention of new therapeutic approaches. For example, small molecule inhibitors of CHOP expression may act as therapeutic options to prevent ER stress and microbial infections. Research had shown that small molecule inhibitors of PERK-eIF2α pathway limit PCV2 virus replication.^[65]

Role in other diseases

The regulation of CHOP expression plays an important role in metabolic diseases and in some cancers through its function in mediating apoptosis. The regulation of CHOP expression could be a potential approach to affecting cancer cells through the induction of apoptosis.^{[51][29][44][74]} In the intestinal epithelium, CHOP has been demonstrated to be downregulated under inflammatory conditions (in inflammatory bowel diseases and experimental models of colitis). In this context, CHOP seems to rather regulate the cell cycle than apoptotic processes.^[75]

Mutations or fusions of CHOP (e.g. with