Practice question

Unfolded protein response is evolutionarily conserved stress signaling program activated when concentration of unfolded polypeptides in ER lumen exceeds buffering capacity of BiP and other chaperones, threatening proteostasis. Under basal conditions, BiP binds lumenal domains of three ER transmembrane sensors keeping them inactive: IRE1 bifunctional kinase-endoribonuclease that upon dimerization autophosphorylates and splices XBP1 mRNA removing 26 nucleotide intron producing active transcription factor inducing chaperones, lipid synthesis and ERAD genes; PERK kinase that phosphorylates eIF2α attenuating global translation initiation while allowing selective ATF4 translation controlling amino acid import, redox defense and pro-apoptotic CHOP; and ATF6 bZIP factor that upon BiP release travels in COPII vesicles to Golgi where Site-1 and Site-2 proteases liberate cytosolic fragment activating folding enzymes and ER expansion genes. Accumulation of misfolded proteins titrates BiP away permitting sensor oligomerization and activation. Lipid bilayer stress and calcium depletion also activate UPR via same sensors. Initial response aims at adaptation restoring homeostasis, but prolonged unresolved stress switches UPR to apoptotic program eliminating compromised cells via CHOP mediated pathways and caspase activation and inflammatory signaling.