Signaling the Unfolded Protein Response from the Endoplasmic Reticulum (2004)

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 PubMed Scopus Google Scholar, Cell Biol. 2002; PubMed Scopus Google the has in the and of the basic of the the of the and the of the and basic of the in the in the The ER protein to be for cell ER stress and as the to signaling Walter P. PubMed Scopus Google Scholar, J. PubMed Scopus Google that eukaryotic cells have the and of signaling in evolved to a of the of has and is in cells and expression is to the cells R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google ER in the ER lumen, ER and a and a in the J. PubMed Scopus Google Scholar, Walter P. J. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google to eukaryotic cells have 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. PubMed Google Scholar, PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google is a transcription with basic leucine in the and a ER to stress Biol. PubMed Scopus Google is to the ER and is in accumulation of unfolded proteins in the ER, the is to the of proteins the ER lumen, to and of proteins, and to the and of the The is transcriptional of and a in and a of specific for signaling is the a the accumulation of unfolded proteins in the ER lumen. the that ER as as a and in activating PERK, and in response to ER stress R.J. J. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google is a and of the protein that to proteins the ER and to or conditions, to the of PERK, and to the accumulation of unfolded proteins, is and to and Cell Biol. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google of to the is to the of that to the to transcription J. 2002; PubMed Scopus Google a for to the in the ER and which the is expression of and with accumulation of unfolded or misfolded protein ER is to alter transcriptional programs through and ER stress and to to of a the the transcription Walter P. PubMed Scopus Google of translational and the of to a transcriptional The protein and transcription the of C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-355Crossref PubMed Scopus (672) Google Scholar, PubMed Scopus Google of the of in such as and a ER stress response that is and for J. Biol. PubMed Scopus Google as a in a transcription the protein and as a of that is a for 2001; PubMed Scopus Google Scholar, R.J. 2001; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google of the UPR, to a a translational As the of in the a protein with a that as a transcription for signaling and accumulation of unfolded protein in the ER lumen, to and to a transcription that to the or of to the is and to a that to the to transcription of unfolded is a that can in the of J. Biol. PubMed Scopus Google of and as of which the of the transcription to to Biol. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, P. Cell Biol. PubMed Scopus Google of the UPR, is to is and to a that to the to transcription of J. 2002; PubMed Scopus Google Scholar, J. PubMed Scopus Google and the processing that the ER-associated protein cholesterol The of protein to the to transcription of for J. PubMed Scopus Google a of and folding a of that for protein and in the ER J. 2002; PubMed Scopus Google Scholar, Biol. PubMed Scopus Google that is in response to ER stress to for 2001; PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of and proteins altered in the cells or Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of ER stress in the of that of in Biol. PubMed Scopus Google that and in pathways and with ER response to ER stress is of of R.J. PubMed Scopus Google is the of the initiation is to of in The is in response to ER stress to protein to the of the ER C. P. R.J. 2001; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google cells in or in to protein ER As a cells to ER stress C. P. R.J. 2001; PubMed Scopus Google that the ER in cells to transcriptional of for of to of of a specific of in response to stress the of of that a transcription for of of in which of the is of the R.J. PubMed Scopus Google This is in cells to expression in response to ER stress and ER of PubMed Scopus Google subsequently transcription of in and and ER C. P. R.J. 2001; PubMed Scopus Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google Scholar, C. PubMed Scopus Google signaling accumulation of unfolded protein in the ER lumen, is and to the of the initiation in such as or can be the unfolded and Cell folding in the of the ER is C. R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google conditions, proteins as unfolded the ER stress is such as of such folding in and or misfolded proteins in the ER through the to the and the PubMed Scopus Google This is called ER-associated and is the of ER-associated misfolded proteins is for is to the UPR, which can in transcription of of ERAD, such as and in Walter P. PubMed Scopus Google The to be in of the the ER a that is for of misfolded in the ER, signaling 2001; PubMed Scopus Google Scholar, C. P. P. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.J. PubMed Scopus Google in the in R.J. PubMed Scopus Google the the of unfolded or misfolded proteins in the ER is of the lead to cell pathways the ER and the (1Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1077) Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google the ER can and which through and the protein to P. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, PubMed Scopus Google is ER-associated of the and cells in to ER J. J. PubMed Scopus Google ER which in to J. J. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google is a transcription that expression of in response to ER stress J. Clin. Invest. 2002; 110: PubMed Scopus Google to expression of transcription through the expression of which subsequently through PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google of the cell and of protein folding load the have evolved the to folding and secretory in response to and that the in is cell of cells to the ER to the in J. Cell Biol. 110: PubMed Scopus Google the transcriptional is for cell J. P. 2001; PubMed Scopus Google cells and in cell and of of the of of in a for the in of P. PubMed Scopus Google cell of to of P. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google Scholar, C. PubMed Scopus Google the that of of and that and to is the and as a protein that in the of PubMed Scopus Google the the that the a cell that prior to of and of is cell the and of and in cells have to be J. Biol. 2002; PubMed Scopus Google signaling is for homeostasis. is to that the as transcriptional of a of glucose-regulated proteins in response to J. PubMed Scopus Google that the for in C. P. R.J. 2001; PubMed Scopus Google Scholar, P. 2001; PubMed Scopus Google and with in have a and P. 2001; PubMed Scopus Google Scholar, C. PubMed Scopus Google with a the a P. 2001; PubMed Scopus Google A that the protein folding in the ER of the has As the protein folding in the ER and the of the to protein as be that to C. P. R.J. 2001; PubMed Scopus Google in such as that which to the ER folding and the a and signaling is for of and has in of the pathways and in of the of the is to in for the and for be to the for the of in the to of the signaling and is that a of and in accumulation of unfolded or misfolded proteins in the ER that to the of As with in signaling of the a of the to which pathways or as a of be which of the that of stress a of for the As a of the and of the UPR, be to for the with accumulation of unfolded or misfolded proteins activating or the signaling as 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 PubMed Scopus Google Scholar, Cell Biol. 2002; PubMed Scopus Google the has in the and of the basic of the the of the and the of the and basic of the in the in the The ER protein to be for cell ER stress and as the to signaling Walter P. PubMed Scopus Google Scholar, J. PubMed Scopus Google that eukaryotic cells have the and of signaling in evolved to a of the of has and is in cells and expression is to the cells R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google ER in the ER lumen, ER and a and a in the J. PubMed Scopus Google Scholar, Walter P. J. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google to eukaryotic cells have 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. PubMed Google Scholar, PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google is a transcription with basic leucine in the and a ER to stress Biol. PubMed Scopus Google is to the ER and is in accumulation of unfolded proteins in the ER, the is to the of proteins the ER lumen, to and of proteins, and to the and of the The is transcriptional of and a in and a of specific for signaling is the a the accumulation of unfolded proteins in the ER lumen. the that ER as as a and in activating PERK, and in response to ER stress R.J. J. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google is a and of the protein that to proteins the ER and to or conditions, to the of PERK, and to the accumulation of unfolded proteins, is and to and Cell Biol. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google of to the is to the of that to the to transcription J. 2002; PubMed Scopus Google a for to the in the ER and which the is expression of The basic of the in the in the The ER protein to be for cell ER stress and as the to signaling Walter P. PubMed Scopus Google Scholar, J. PubMed Scopus Google that eukaryotic cells have the and of signaling in evolved to a of the of has and is in cells and expression is to the cells R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google ER in the ER lumen, ER and a and a in the J. PubMed Scopus Google Scholar, Walter P. J. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google to eukaryotic cells have 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. PubMed Google Scholar, PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google is a transcription with basic leucine in the and a ER to stress Biol. PubMed Scopus Google is to the ER and is in cells. accumulation of unfolded proteins in the ER, the is to the of proteins the ER lumen, to and of proteins, and to the and of the The is transcriptional of and a in and a of specific for signaling is the a the accumulation of unfolded proteins in the ER lumen. the that ER as as a and in activating PERK, and in response to ER stress R.J. J. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google is a and of the protein that to proteins the ER and to or conditions, to the of PERK, and to the accumulation of unfolded proteins, is and to and Cell Biol. PubMed Scopus Google Scholar, R.J. J. Biol. PubMed Scopus Google of to the is to the of that to the to transcription J. 2002; PubMed Scopus Google a for to the in the ER and which the is expression of and with accumulation of unfolded or misfolded protein ER is to alter transcriptional programs through and ER stress and to to of a the the transcription Walter P. PubMed Scopus Google of translational and the of to a transcriptional The protein and transcription the of C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-355Crossref PubMed Scopus (672) Google Scholar, PubMed Scopus Google of the of in such as and a ER stress response that is and for J. Biol. PubMed Scopus Google as a in a transcription the protein and as a of that is a for 2001; PubMed Scopus Google Scholar, R.J. 2001; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google of the UPR, to a a translational As the of in the a protein with a that as a transcription for is a that can in the of J. Biol. PubMed Scopus Google of and as of which the of the transcription to to Biol. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, P. Cell Biol. PubMed Scopus Google of the UPR, is to is and to a that to the to transcription of J. 2002; PubMed Scopus Google Scholar, J. PubMed Scopus Google and the processing that the ER-associated protein cholesterol The of protein to the to transcription of for J. PubMed Scopus Google a of and folding a of that for protein and in the ER J. 2002; PubMed Scopus Google Scholar, Biol. PubMed Scopus Google that is in response to ER stress to for 2001; PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of and proteins altered in the cells or Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of ER stress in the of that of in Biol. PubMed Scopus Google that and in pathways and with ER with accumulation of unfolded or misfolded protein ER is to alter transcriptional programs through and ER stress and to to of a the the transcription Walter P. PubMed Scopus Google of translational and the of to a transcriptional The protein and transcription the of C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-355Crossref PubMed Scopus (672) Google Scholar, PubMed Scopus Google of the of in such as and a ER stress response that is and for J. Biol. PubMed Scopus Google as a in a transcription the protein and as a of that is a for 2001; PubMed Scopus Google Scholar, R.J. 2001; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google of the UPR, to a a translational As the of in the a protein with a that as a transcription for is a that can in the of J. Biol. PubMed Scopus Google of and as of which the of the transcription to to Biol. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, P. Cell Biol. PubMed Scopus Google of the UPR, is to is and to a that to the to transcription of J. 2002; PubMed Scopus Google Scholar, J. PubMed Scopus Google and the processing that the ER-associated protein cholesterol The of protein to the to transcription of for J. PubMed Scopus Google a of and folding a of that for protein and in the ER J. 2002; PubMed Scopus Google Scholar, Biol. PubMed Scopus Google that is in response to ER stress to for 2001; PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of and proteins altered in the cells or Biol. PubMed Scopus Google Scholar, R.J. 2002; PubMed Scopus Google of ER stress in the of that of in Biol. PubMed Scopus Google that and in pathways and with ER response to ER stress is of of R.J. PubMed Scopus Google is the of the initiation is to of in The is in response to ER stress to protein to the of the ER C. P. R.J. 2001; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google cells in or in to protein ER As a cells to ER stress C. P. R.J. 2001; PubMed Scopus Google that the ER in cells to transcriptional of for of to of of a specific of in response to stress the of of that a transcription for of of in which of the is of the R.J. PubMed Scopus Google This is in cells to expression in response to ER stress and ER of PubMed Scopus Google subsequently transcription of in and and ER C. P. R.J. 2001; PubMed Scopus Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google Scholar, C. PubMed Scopus Google The response to ER stress is of of R.J. PubMed Scopus Google is the of the initiation is to of in The is in response to ER stress to protein to the of the ER C. P. R.J. 2001; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google cells in or in to protein ER As a cells to ER stress C. P. R.J. 2001; PubMed Scopus Google that the ER in cells to transcriptional of for of to of of a specific of in response to stress the of of that a transcription for of of in which of the is of the R.J. PubMed Scopus Google This is in cells to expression in response to ER stress and ER of PubMed Scopus Google subsequently transcription of in and and ER C. P. R.J. 2001; PubMed Scopus Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google Scholar, C. PubMed Scopus Google ER and Cell folding in the of the ER is C. R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google conditions, proteins as unfolded the ER stress is such as of such folding in and or misfolded proteins in the ER through the to the and the PubMed Scopus Google This is called ER-associated and is the of ER-associated misfolded proteins is for is to the UPR, which can in transcription of of ERAD, such as and in Walter P. PubMed Scopus Google The to be in of the the ER a that is for of misfolded in the ER, signaling 2001; PubMed Scopus Google Scholar, C. P. P. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.J. PubMed Scopus Google in the in R.J. PubMed Scopus Google the the of unfolded or misfolded proteins in the ER is of the lead to cell pathways the ER and the (1Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1077) Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google the ER can and which through and the protein to P. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, PubMed Scopus Google is ER-associated of the and cells in to ER J. J. PubMed Scopus Google ER which in to J. J. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google is a transcription that expression of in response to ER stress J. Clin. Invest. 2002; 110: PubMed Scopus Google to expression of transcription through the expression of which subsequently through PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google folding in the of the ER is C. R.J. PubMed Scopus Google Scholar, J. PubMed Scopus Google conditions, proteins as unfolded the ER stress is such as of such folding in and or misfolded proteins in the ER through the to the and the PubMed Scopus Google This is called ER-associated and is the of ER-associated misfolded proteins is for is to the UPR, which can in transcription of of ERAD, such as and in Walter P. PubMed Scopus Google The to be in of the the ER a that is for of misfolded in the ER, signaling 2001; PubMed Scopus Google Scholar, C. P. P. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.J. PubMed Scopus Google in the in R.J. PubMed Scopus Google the the of unfolded or misfolded proteins in the ER is of the lead to cell pathways the ER and the (1Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1077) Google Scholar, J. Clin. Invest. 2002; 110: PubMed Scopus Google the ER can and which through and the protein to P. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, PubMed Scopus Google is ER-associated of the and cells in to ER J. J. PubMed Scopus Google ER which in to J. J. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google is a transcription that expression of in response to ER stress J. Clin. Invest. 2002; 110: PubMed Scopus Google to expression of transcription through the expression of which subsequently through PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google of the cell and of protein folding load the have evolved the to folding and secretory in response to and that the in is cell of cells to the ER to the in J. Cell Biol. 110: PubMed Scopus Google the transcriptional is for cell J. P. 2001; PubMed Scopus Google cells and in cell and of of the of of in a for the in of P. PubMed Scopus Google cell of to of P. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google Scholar, C. PubMed Scopus Google the that of of and that and to is the and as a protein that in the of PubMed Scopus Google the the that the a cell that prior to of and of is cell the and of and in cells have to be J. Biol. 2002; PubMed Scopus Google signaling is for homeostasis. is to that the as transcriptional of a of glucose-regulated proteins in response to J. PubMed Scopus Google that the for in C. P. R.J. 2001; PubMed Scopus Google Scholar, P. 2001; PubMed Scopus Google and with in have a and P. 2001; PubMed Scopus Google Scholar, C. PubMed Scopus Google with a the a P. 2001; PubMed Scopus Google A that the protein folding in the ER of the has As the protein folding in the ER and the of the to protein as be that to C. P. R.J. 2001; PubMed Scopus Google in such as that which to the ER folding and the a and signaling is for of and cell and of protein folding load the have evolved the to folding and secretory in response to and that the in is cell of cells to the ER to the in J. Cell Biol. 110: PubMed Scopus Google the transcriptional is for cell J. P. 2001; PubMed Scopus Google cells and in cell and of of the of of in a for the in of P. PubMed Scopus Google cell of to of P. PubMed Scopus Google Scholar, J. Biol. 2002; PubMed Scopus Google Scholar, C. PubMed Scopus Google the that of of and that and to is the and as a protein that in the of PubMed Scopus Google the the that the a cell that prior to of and of is cell the and of and in cells have to be J. Biol. 2002; PubMed Scopus Google signaling is for homeostasis. is to that the as transcriptional of a of glucose-regulated proteins in response to J. PubMed Scopus Google that the for in C. P. R.J. 2001; PubMed Scopus Google Scholar, P. 2001; PubMed Scopus Google and with in have a and P. 2001; PubMed Scopus Google Scholar, C. PubMed Scopus Google with a the a P. 2001; PubMed Scopus Google A that the protein folding in the ER of the has As the protein folding in the ER and the of the to protein as be that to C. P. R.J. 2001; PubMed Scopus Google in such as that which to the ER folding and the a and signaling is for of and has in of the pathways and in of the of the is to in for the and for be to the for the of in the to of the signaling and is that a of and in accumulation of unfolded or misfolded proteins in the ER that to the of As with in signaling of the a of the to which pathways or as a of be which of the that of stress a of for the As a of the and of the UPR, be to for the with accumulation of unfolded or misfolded proteins activating or the signaling as has in of the pathways and in of the of the is to in for the and for be to the for the of in the to of the signaling and is that a of and in accumulation of unfolded or misfolded proteins in the ER that to the of As with in signaling of the a of the to which pathways or as a of be which of the that of stress a of for the As a of the and of the UPR, be to for the with accumulation of unfolded or misfolded proteins activating or the signaling as for