1 MISFOLDED PROTEINS IN ER SIGNAL THE NEED FOR MORE ER CHAPERONES. THEY BIND TO AND ACTIVATE A TRANSMEMBRANE KINASE 2 ACTIVATED KINASE UNMASKS AN ENDORIBONUCLEASE ACTIVITY 3 ENDORIBONUCLEASE CUTS SPECIFIC RNA MOLECULES AT TWO POSITIONS, REMOVING AN INTRON 6 TRANSCRIPTION REGULATOR ENTERS NUCLEUS AND ACTIVATES GENES ENCODING ER CHAPERONES 7 CHAPERONES ARE MADE IN ER, WHERE THEY HELP FOLD PROTEINS 4 TWO EXONS ARE LIGATED TO FORM AN ACTIVE mRNA 5 mRNA IS TRANSLATED TO MAKE A TRANSCRIPTION REGULATOR similar way, as discussed in Chapter 15.) The oligomerization and autophosphorylation of IRE1 activates an endoribonuclease domain in the cytosolic portion of the same molecule, which cleaves a specific cytosolic mRNA molecule at two positions, excising an intron. (This is a unique exception to the rule that introns are spliced out while the RNA is still in the nucleus.) The separated exons are then joined by an RNA ligase, generating a spliced mRNA, which is translated to produce an active transcription regulatory protein. This protein activates the transcription of genes encoding the proteins that help mediate the unfolded protein response (Figure 12–51B).
Misfolded proteins also activate a second transmembrane kinase in the ER, PERK, which inhibits a translation initiation factor by phosphorylating it, thereby reducing the production of new proteins throughout the cell. One consequence of the reduction in protein synthesis is to reduce the flux of proteins into the ER, thereby reducing the load of proteins that need to be folded there. Some proteins, however, are preferentially translated when translation initiation factors are scarce (discussed in Chapter 7, p. 424), and one of these is a transcription regulator that helps activate the transcription of the genes encoding proteins active in the unfolded protein response.
Finally, a third transcription regulator, ATF6, is initially synthesized as a trans-membrane ER protein. Because it is embedded in the ER membrane, it cannot activate the transcription of genes in the nucleus. When misfolded proteins accumulate in the ER, however, the ATF6 protein is transported to the Golgi apparatus, where it encounters proteases that cleave off its cytosolic domain, which can now migrate to the nucleus and help activate the transcription of genes encoding proteins involved in the unfolded protein response. (This mechanism is similar to that described in Figure 12–16 for activation of the transcription regulator that controls cholesterol biosynthesis.) The relative importance of each of these three pathways in the unfolded protein response differs in different cell types, enabling each cell type to tailor the unfolded protein response to its particular needs.
As discussed in Chapter 10, several cytosolic enzymes catalyze the covalent addition of a single fatty acid chain or prenyl group to selected proteins. The attached lipids help direct and attach these proteins to cell membranes. A related process is catalyzed by ER enzymes that covalently attach a glycosylphosphatidylinositol (GPI) anchor to the C-terminus of some membrane proteins destined for the plasma membrane. This linkage forms in the lumen of the ER, where, at the same time, the transmembrane segment of the protein is cleaved off (Figure 12–52). A large number of plasma membrane proteins are modified in this way. Since they are attached to the exterior of the plasma membrane only by their GPI anchors,