Evolutionary Aspects of the Unfolded Protein Response

The unfolded protein response (UPR) is activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). The basic mechanism of the UPR in maintaining ER homeostasis has been clarified from yeast to humans. The UPR is triggered by one or more transmembrane proteins in the ER. The number of canonical UPR sensors/transducers has increased during evolution, from one (IRE1) in yeast to three (IRE1, PERK, and ATF6) in invertebrates and five (IRE1α, IRE1β, PERK, ATF6α, and ATF6β) in vertebrates. Here, I initially describe the four major changes that have occurred during evolution: (1) advent of PERK in metazoans; (2) switch in transcription factor downstream of IRE1 in metazoans; (3) switch in regulator of ER chaperone induction in vertebrates; and (4) increase in the number of ATF6-like local factors in vertebrates. I then discuss the causes of the phenotypes of vertebrate knockout animals and refer to regulated IRE1-dependent decay of mRNAs.