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. 2017 Nov 27;8:1612. doi: 10.3389/fimmu.2017.01612

Figure 2.

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.