Signaling the Unfolded Protein Response from the Endoplasmic Reticulum

Abstract

Eukaryotic cells have a membranous labyrinth network called the endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; UPR, unfolded protein response; IRE, inositol-requiring enzyme; ATF, activating transcription factor; PERK, double-stranded RNA-activated protein kinase-like ER kinase; XBP, X-box-binding protein; UPRE, unfolded protein response element; ERSE, ER stress response element; eIF, eukaryotic initiation factor; b-ZIP, basic leucine zipper; ERAD, ER-associated degradation; GRP, glucose-regulated protein.1The abbreviations used are: ER, endoplasmic reticulum; UPR, unfolded protein response; IRE, inositol-requiring enzyme; ATF, activating transcription factor; PERK, double-stranded RNA-activated protein kinase-like ER kinase; XBP, X-box-binding protein; UPRE, unfolded protein response element; ERSE, ER stress response element; eIF, eukaryotic initiation factor; b-ZIP, basic leucine zipper; ERAD, ER-associated degradation; GRP, glucose-regulated protein. that extends through the cytoplasm of the cell and is contiguous with the nuclear envelope. Proteins must be correctly folded and assembled in the ER prior to transit to intracellular organelles and the cell surface. As a processing plant for protein folding and posttranslational modification, the ER is exquisitely sensitive to alterations in homeostasis. A number of cellular stress conditions, such as perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, altered glycosylation, and overloading of cholesterol can interfere with oxidative protein folding and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen, which constitutes a fundamental threat to the cells. The ER has evolved highly specific signaling pathways to alter transcriptional and translational programs to cope with the accumulation of unfolded or misfolded proteins in the ER lumen. This adaptive response, which couples the ER protein folding load with the ER protein folding capacity, is termed the unfolded protein response (UPR) (1Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1077) Google Scholar, 2Patil C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-355Crossref PubMed Scopus (672) Google Scholar, 3Mori K. Cell. 2000; 101: 451-454Abstract Full Text Full Text PDF PubMed Scopus (784) Google Scholar, 4Harding H.P. Calfon M. Urano F. Novoa I. Ron D. Annu. Rev. Cell Dev. Biol. 2002; 18: 575-599Crossref PubMed Scopus (800) Google Scholar). Over the past 10 years, significant progress has been made in understanding the mechanisms and roles of UPR signaling. Here we discuss the basic components of the UPR pathways, the physiological roles of the UPR signaling, and the future direction of the field.Three UPR Transducers and One Master RegulatorThe basic components of the UPR pathway were first characterized in the budding yeast Saccharomyces cerevisiae in the early 1990s. The ER transmembrane protein kinase/endoribonuclease Ire1p/Ern1p was found to be essential for cell survival during ER stress and was identified as the transducer to initiate UPR signaling (5Cox J.S. Shamu C.E. Walter P. Cell. 1993; 73: 1197-1206Abstract Full Text PDF PubMed Scopus (923) Google Scholar, 6Mori K. Ma W. Gething M.-J. Sambrook J. Cell. 1993; 74: 743-756Abstract Full Text PDF PubMed Scopus (646) Google Scholar). Thereafter, researchers found that eukaryotic cells have the essential and of UPR signaling identified in yeast evolved to a of the of yeast has and is in cells and expression is to the cells W. R.J. Dev. PubMed Scopus Google Scholar, H.P. M. Ron D. J. PubMed Scopus Google Scholar). ER in the ER lumen, ER transmembrane and a and a in the K. Ma W. Gething M.-J. Sambrook J. Cell. 1993; 74: 743-756Abstract Full Text PDF PubMed Scopus (646) Google Scholar, C.E. Walter P. J. PubMed Scopus Google Scholar, R.J. J. Biol. Full Text Full Text PDF PubMed Scopus Google to eukaryotic cells have UPR the double-stranded RNA-activated protein kinase-like ER and activating transcription a ER that is with the and a that the of eukaryotic initiation J. J. Cell Biol. 18: PubMed Google Scholar, H.P. Ron D. PubMed Scopus Google Scholar, M. R.J. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is a transcription with basic leucine in the and a ER to stress K. K. Biol. Cell. PubMed Scopus Google Scholar). UPR transducer is to the ER and is in accumulation of unfolded proteins in the ER, the UPR is to the of proteins the ER lumen, to and of proteins, and to the and of the The UPR is transcriptional of and a in and a of specific essential for UPR signaling is the a the accumulation of unfolded proteins in the ER lumen. the that ER as as a UPR and essential roles in activating PERK, and in response to ER stress R.J. J. PubMed Scopus Google Scholar, H.P. Ron D. Cell Biol. 2000; PubMed Scopus Google Scholar, J. Dev. Cell. 2002; Ful