Transcription Factor C/EBP Homologous Protein in Health and Diseases

Abstract

C/EBP homologous protein (CHOP), known also as DNA damage-inducible transcript 3 and as growth arrest and DNA damage-inducible protein 153 (GADD153), is induced in response to certain stressors. CHOP is universally acknowledged as a main conduit to endoplasmic reticulum stress-induced apoptosis. Ongoing research established the existence of CHOP-mediated apoptosis signaling networks, for which novel downstream targets are still being determined. However, there are studies that contradict this notion and assert that apoptosis is not the only mechanism by which CHOP plays in the development of pathologies. In this review, insights into the roles of CHOP in pathophysiology are summarized at the molecular and cellular levels. We further focus on the newest advances that implicate CHOP in human diseases including cancer, diabetes, neurodegenerative disorders, and notably, fibrosis.

Keywords: C/EBP homologous protein; apoptosis; cancer; diabetes; endoplasmic reticulum stress; fibrosis; neurodegenerative disorders.

Figure 1

CHOP structure. CHOP is a protein containing 169 amino acids that divide into N-terminus transcriptional activation/repression domains and a C-terminus bZIP domain including a basic region for DNA binding and a leucine zipper region for dimerization. The motif between aa 10 and 18 is for interaction with TRB3. The transactivation domain contains a serine residue (30) that is phosphorylated by AMPKα1 to trigger the proteasomal degradation of CHOP in macrophages. It is also degraded by SPOP that recognizes the serine/threonine-rich motif between aa 97 and 100. Phosphorylation at two serine residues (79, 82) by p38 MAPK enhances the transcriptional activation by CHOP. The basic region holds glycine (109) and proline (112) substitutions interrupting the DNA-binding activity. CHOP, C/EBP homologous protein; bZIP, basic-leucine zipper; SPOP, speckle-type POZ protein; p38 MAPK, p38 mitogen-activation protein kinase; aa, amino acid.

Figure 2

Regulation of CHOP. The three signaling branches of UPR lead to CHOP transcription respectively. Once activated via dimerization and trans-autophosphorylation, PERK phosphorylates eIF2α, which enables ATF4 translation. Subsequently, CHOP is activated by ATF4 trafficking to the nucleus. In the presence of misfolded proteins, ATF6α translocates to the Golgi apparatus where it was processed by the protease SP1 and SP2, thus producing a cytosolic fragment ATF6f to regulate CHOP activation in the nucleus. Activation of IRE1α RNase domain processes unspliced XBP1 mRNA to create activated XBP1(s), which enters the nucleus and controls the expression of CHOP. Another pathway involves ISR. This response is initiated with GCN2, PKR, HRI, and PEAK that converge on the phospho-eIF2α/ATF4 pathway and CHOP induction ensues. A ROS-dependent mechanism also activates CHOP via MAPKs. CHOP, C/EBP homologous protein; UPR, unfolded protein response; ISR, integrated stress response; ATF, activating transcription factor; ATF6α, activating transcription factor 6α; PERK, PRKR-like ER kinase; XBP1, X box-binding protein 1; GCN2, general control nonderepressible 2; PKR, RNA-dependent protein kinase; HRI, heme regulated inhibitor; ROS, reactive oxygen species; MAPKs, mitogen-activated protein kinases; eIF2α, eukaryotic translation initiator factor 2α.

Figure 3

Model depicting targets of CHOP-dependent apoptosis. During chronic ER stress, CHOP activation mediates pro-apoptosis signaling via numerous targets and pathways directly or indirectly. CHOP triggers the intrinsic apoptotic pathway through inhibition of BCL-2 and upregulation of BIM and PUMA, which regulate BAX–BAK-mediated mitochondrial outer membrane permeabilization. This leads to cytochrome c release and caspase cascade. CHOP also directly induces the expression of DR5-mediating extrinsic apoptotic pathway via FADD and caspase8-mediated cascade. In normal conditions, CHOP-dependent ERO1α induction oxidizes PDI to produce ROS that plays a critical role in apoptosis. The ERO1α–IP3R–Ca²⁺–CaMKII pathway, in addition to ROS, can trigger several apoptotic pathways, primarily the Ca²⁺-dependent mitochondrial apoptosis via PTP. GADD34 is a key target of CHOP and ATF4 and combines with PP1 to promote dephosphorylation of phospho-eIF2α. This event renews protein translation that promotes apoptosis in certain stress settings. Another target is TRB3 that prevent Akt phosphorylation in this apoptotic pathway. ATF5, downstream of CHOP, facilitates apoptosis through activation of some pro-apoptotic genes, such as NOXA. CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; ATF, activating transcription factor; ROS, reactive oxygen species; DR5, death receptor 5; FADD, Fas-associated death domain; GADD34, growth arrest and DNA-damage-inducible protein 34; PP1, protein phosphatase 1; PDI, protein disulfide isomerase; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; TRB3, tribbles-related protein 3; ERO1α, ER oxidase 1α.