Multiple translocator complexes move different proteins from the ER membrane or lumen into the cytosol. A common feature is that they each contain an E3 ubiquitin ligase enzyme, which attaches polyubiquitin tags to the unfolded proteins as they emerge into the cytosol, marking them for destruction. Fueled by the energy derived from ATP hydrolysis, a hexomeric ATPase of the family of AAA-ATPases (see Figure 6–85) pulls the unfolded protein through the translocator into the cytosol. An N-glycanase removes its oligosaccharide chains en bloc. Guided by its ubiquitin tag, the deglycosylated polypeptide is rapidly fed into proteasomes, where it is degraded (Figure 12–50).
misfolded proteins in the er activate an Unfolded protein response
Cells carefully monitor the amount of misfolded protein in various compartments. An accumulation of misfolded proteins in the cytosol, for example, triggers a heat-shock response (discussed in Chapter 6), which stimulates the transcription of genes encoding cytosolic chaperones that help to refold the proteins. Similarly, an accumulation of misfolded proteins in the ER triggers an unfolded protein response, which includes an increased transcription of genes encoding proteins involved in retrotranslocation and protein degradation in the cytosol, ER chaperones, and many other proteins that help to increase the protein-folding capacity of the ER.
Figure 12–50 The export and degradation of misfolded ER proteins.
misfolded soluble proteins in the er lumen are recognized and targeted to a translocator complex in the er membrane. They first interact in the er lumen with chaperones, disulfide isomerases, and lectins. They are then exported into the cytosol through the translocator. in the cytosol, they are ubiquitylated, deglycosylated, and degraded in proteasomes. misfolded membrane proteins follow a similar pathway but  use a different translocator.
How do misfolded proteins in the ER signal to the nucleus? There are three parallel pathways that execute the unfolded protein response (Figure 12–51A). The first pathway, which was initially discovered in yeast cells, is particularly remarkable. Misfolded proteins in the ER activate a transmembrane protein kinase in the ER, called IRE1, which causes the kinase to oligomerize and phosphorylate itself. (Some cell-surface receptor kinases in the plasma membrane are activated in a
Figure 12–51 The unfolded protein response. (a) By three parallel intracellular signaling pathways, the accumulation of misfolded proteins in the er lumen signals to the nucleus to activate the transcription of genes that encode proteins that help the cell cope with misfolded proteins in the er. (B) regulated rna splicing is a key regulatory switch in pathway 1 of the unfolded protein response (Movie 12.6).