Title:
Protein Quality Control by the Unfolded Protein Response

 

Kazutoshi Mori,
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan

 

Abstract:
Proteins are linear polypeptides when synthesized according to the “central dogma” and must be folded to fulfill their functions as assigned by genetic code. Secretory and transmembrane proteins are folded in the endoplasmic reticulum (ER), which contains molecular chaperones and folding enzymes (ER chaperones) abundantly, and only correctly folded molecules are allowed to move along the secretory pathway. In 1988, Mary-Jane Gething and Joe Sambrook showed that accumulation of unfolded or misfolded proteins in the ER (ER stress) triggered transcriptional induction of ER chaperones, resulting in augmentation of folding capacity in the ER, and designated this homeostatic response the Unfolded Protein Response (UPR). I became a post-doc in their labs in 1989 and started to analyze the mechanism of the UPR. Peter Walter and I revealed that yeast UPR consists of the IRE1-HAC1 pathway¹⁾. Randy Kaufman and David Ron identified IRE1α and IRE1β, respectively, as mammalian homologs of yeast IRE1. I and David Ron showed that XBP1 is a transcription factor downstream of mammalian IRE1. David Ron and I identified PERK and ATF6, respectively, as the second and third mammalian ER stress sensors. Interestingly, transcriptional induction of ER chaperones in response to ER stress is mediated by the IRE1 pathway in invertebrates but by the ATF6 pathway in vertebrates²⁾. I am now make an effort toward comprehensive understanding of the UPR using medaka fish, a vertebrate model, that is to understand what is physiological ER stress and why we need so many ER stress sensors³⁾.

 

References:
1) Mori, K. (2015). The unfolded protein response: the dawn of a new field. Proc. Jpn Acad. Ser. B 91, 469-480.
2) Mori, K. (2009). Signalling pathways in the unfolded protein response: development from yeast to mammals. J. Biochem. 146, 743-750.
3) Ishikawa, T. et al. (2013). ATF6alpha/beta-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish. Mol. Biol. Cell 24, 1387-1395.