Figure 3.

The UPR downstream signaling pathway. The UPR signal transducers, PERK, IRE1, and ATF6, are bounded by GRP78 under the normal condition. The accumulation of misfolded proteins triggers GRP78 to release and activate the UPR signal transducers to bind to the misfolded proteins, hence activating the UPR downstream signaling pathways. In the IRE1 pathway, IRE1 cleaves and releases XBP1 mRNA, which is translated to the active XBP1 protein that enhances the expression of UPR target genes. Meanwhile, PERK phosphorylates eIF2 and inhibits general mRNA translation, while upregulating the gene expression of resident ER proteins, hence reducing the ER workload to relieve the ERS. On the other hand, ATF6 migrates to the Golgi apparatus and is cleaved by the S1P and S2P protein, to expose its bZIP domain. Activated ATF6 is translocated to the nucleus and acts as a transcription factor to enhance the gene expressions of several ER resident proteins that contribute to protein folding, secretion, modification, and ERAD processes. * bZIP, Basic Leucine Zipper; eIF2, Eukaryotic Initiation Factor 2; ERAD, ER-associated Degradation; S1P, Sphingosine-1-Phosphate; S2P, Sphingosine-2-Phosphate.