Figure 8

The mechanism and signaling pathways of BiPs involved in protein synthesis and diverse defense responses. BiP binds to nascent protein peptides, to prevent degradation or misfolding. Peptides are folded and assembled, form ER protein bodies (ER-PB), and are transported out of the ER with assistance from BiP. Misfolded or unfolded proteins are transported to the cytosol for degradation with the help of BiP. Under non-stressed conditions, BiP binds to the lumenal domains of analogous IRE1 to prevent their dimerization. When the ER is stressed, analogous ATF6 or bZiP60 released from BiP is transported to the Golgi compartment, where cleavage by TMD yields a cytosolic fragment that migrates to the nucleus to further activate transcription of UPR-responsive genes. Similarly, IRE1 released from BiP dimerizes to activate its kinase and RNAase activities to initiate XBP1 mRNA splicing, thereby creating a potent transcriptional activator to induce the gene encoding functions for ERAD. Finally, analogous PERK released from BiP dimerizes, and activates eIF2α, which leads to general attenuation of translational initiation, while eIF2α phosphorylation induces translation of ATF4 mRNA. The PERK/eIF2α/ATF4 regulatory axis thus induces expression of anti-stress response genes.