Skip to main content
NCBI home page
Cold Spring Harbor Perspectives in Biology logoLink to Cold Spring Harbor Perspectives in Biology
. 2022 Dec;14(12):a041262. doi: 10.1101/cshperspect.a041262

Evolutionary Aspects of the Unfolded Protein Response

Kazutoshi Mori 1
PMCID: PMC9732898  PMID: 35940910

Abstract

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.

Protein unfolding and misfolding constitute a fundamental threat to all living cells. In eukaryotes, proteins can be unfolded or misfolded in various subcellular compartments such as the cytoplasm and mitochondria, but the risk of misfolding is particularly high in the endoplasmic reticulum (ER). Newly synthesized secretory and transmembrane proteins destined for the secretory pathway achieve their proper tertiary and quaternary structure in the ER. These proteins are critical for intercellular communication and undergo productive folding inside the ER, assisted by ER-localized molecular chaperones and folding enzymes (ER chaperones hereafter). Only correctly folded molecules can move along the secretory pathway. Proteins that fail to fold correctly or that misfold despite assistance from ER chaperones are subjected to ER-associated degradation (ERAD), which degrades such proteins using the ubiquitin-dependent proteasome system in the cytoplasm. Together, these two mechanisms with opposing outcomes, productive folding and ERAD, ensure the quality of proteins that pass through the ER (Bukau et al. 2006; Wu and Rapoport 2018; Ninagawa et al. 2021).

Regardless, this ER quality control system can fail under a variety of physiological and pathological conditions. Failure results in unfolded or misfolded proteins accumulating within the ER, and therefore, ER stress. Nearly all eukaryotic cells cope with ER stress by activating highly sophisticated transcriptional and translational programs, collectively termed the unfolded protein response (UPR) (Fig. 1; Mori 2000; Ron and Walter 2007). (1) Translation is generally attenuated to decrease the burden on the ER via phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), which is critical for determining the rate of translational initiation (Harding et al. 2002). (2) Transcription of genes encoding ER chaperones is induced to increase folding capacity in the ER (Kozutsumi et al. 1988). (3) Transcription of genes encoding ERAD components, which detect and process proteins misfolded in the ER for retrotranslocation to the cytoplasm, is induced to augment degradation capacity (Travers et al. 2000). Two cis-acting ER stress-responsive DNA elements have been identified. The first is the ER stress response element (ERSE), which has the sequence CCAAT-N9-CCACG, and is responsible for transcriptional induction of ER chaperones (Yoshida et al. 1998). The second is the UPR element (UPRE), which has the sequence TGACGTGG/A, and is involved in transcriptional induction of genes encoding ERAD components (Yoshida et al. 2001a). (4) If ER stress is prolonged, the cell eventually undergoes apoptosis (Fig. 1).

Figure 1.

Figure 1.

Open in a new tab

Basic mechanism of mammalian unfolded protein response (UPR).

ER stress is sensed by one or more transmembrane proteins in the ER, which triggers a downstream signaling cascade to restore homeostasis of the ER (Mori 2009; Walter and Ron 2011). Intriguingly, the number of canonical sensors/transducers appears to have increased during evolution (Fig. 2). IRE1, the most highly conserved sensor/transducer, has been identified in all eukaryotes. PERK appears to be exclusive to metazoans. ATF6 is also found in metazoans but has a novel function in vertebrates as a transcription factor activated by ER stress-induced proteolysis. In addition, four notable changes have occurred in the UPR; these changes are the main focus of this review.

Figure 2.

Figure 2.

Open in a new tab

Four changes that have occurred during evolution. (Hs) Homo sapiens, (Mm) Mus musculus, (Ol) Oryzias latipes. BBF2H7 and OASIS are orthologs of CREB/ATF-a (Ciona intestinalis), whereas CREB-H, Tisp40, and LUMAN are orthologs of CREB/ATF-b (C. intestinalis).

UPR BASIC MOLECULAR MECHANISM

IRE1 Pathway

IRE1 is an ER-localized type I transmembrane protein that has both a protein kinase domain (depicted by the yellow circle) and an endoribonuclease domain (RNase, depicted by a part of the orange star) on its cytosolic side (Figs. 1 and 2). Although yeast and invertebrate animals possess a single IRE1 gene (Cox et al. 1993; Mori et al. 1993; Shen et al. 2005; Hollien and Weissman 2006), vertebrates have two IRE1 paralogs, IRE1α and IRE1β. In mammals, IRE1α is ubiquitous while IRE1β is gut-specific (Tirasophon et al. 1998; Wang et al. 1998). In medaka fish, a vertebrate model organism, both paralogs are ubiquitous (Ishikawa et al. 2011).

The downstream transcription factor of IRE1 is encoded by HAC1 in yeast and XBP1 in metazoans (Fig. 2). In metazoans, upon activation in response to ER stress via oligomerization and autophosphorylation, IRE1 initiates spliceosome-independent unconventional splicing (frame switch splicing) of XBP1 mRNA, and the spliced transcript is translated into XBP1(S) (S stands for spliced form) (Yoshida et al. 2001a; Calfon et al. 2002). In contrast, constitutively expressed unspliced XBP1 mRNA is translated into XBP1(U) (U stands for unspliced form); the IRE1 RNase domain cleaves unspliced XBP1 mRNA at two characteristic stem-loop structures (Fig. 3). XBP1(S) and XBP1(U) share the same amino-terminal region that contains a basic leucine zipper (bZIP)-type DNA-binding domain but differ in their carboxy-terminal regions (Fig. 3). The carboxy-terminal region of XBP1(S) contains a transcriptional activation domain (depicted as a red box). XBP1(S) therefore functions as a highly active transcription factor via binding to both ERSE and UPRE (Yoshida et al. 2001a). Since the carboxy-terminal region of XBP1(U) contains a degron (depicted as a blue box), XBP1(U) instead functions as a negative regulator of XBP1(S) (Yoshida et al. 2006), and ATF6(N) (see below for ATF6(N); Yoshida et al. 2009).

Figure 3.

Figure 3.

Open in a new tab

Three independent signals from IRE1.

UPRE was originally called the ATF6 site, because it was selected from among random oligonucleotides as a sequence that can bind to the purified bZIP domain of ATF6 in vitro (Wang et al. 2000). However, the ATF6 site was demonstrated to be the preferential binding site of XBP1 both in vitro and in the cell (Yoshida et al. 2001a). Accordingly, the ATF6 site was renamed UPRE to indicate that it is the binding site of the transcription factors HAC1 and XBP1, which are regulated in a similar fashion by IRE1-mediated unconventional mRNA splicing.

PERK Pathway

Metazoans express a single PERK, a type I transmembrane protein with a kinase domain (depicted by the pink box) on its cytosolic side (Figs. 1 and 2). Following activation in response to ER stress via oligomerization and autophosphorylation, PERK phosphorylates eIF2α, thereby decreasing the burden on the ER via attenuated translation (Fig. 1; Harding et al. 1999). Paradoxically, attenuated translation leads to translational induction of certain mRNAs, including ATF4, which encodes the transcription factor ATF4. ATF4 targets include genes involved in amino acid metabolism and resistance to oxidative stress, as well as the gene that encodes the proapoptotic transcription factor CHOP (Harding et al. 2000, 2003). Importantly, CHOP induces GADD34 transcription, resulting in recruitment of protein phosphatase 1C, which dephosphorylates eIF2α (Marciniak et al. 2004). Thus, translation levels attenuated by activated PERK return to normal with time (Novoa et al. 2001).

ATF6 Pathway

Invertebrates possess a single ATF6 gene, whereas mammals and medaka fish both have two ubiquitously expressed ATF6 paralogs, ATF6α and ATF6β (Figs. 1 and 2; Yamamoto et al. 2007; Ishikawa et al. 2011). ATF6α and ATF6β are constitutively synthesized as type II transmembrane proteins, designated ATF6α(P) and ATF6β(P) (P stands for precursor form) (Haze et al. 1999, 2001). These molecules translocate from the ER to the Golgi apparatus via COPII vesicles in response to ER stress. Both precursor proteins are cleaved sequentially by two proteases, site-1 protease (S1P) and site-2 protease (S2P) in the Golgi apparatus (Fig. 1; Ye et al. 2000; Nadanaka et al. 2004). Since ATF6α(N) and ATF6β(N) (N stands for nuclear form) liberated from the Golgi membrane contain DNA-binding and transcriptional activation domains, they can activate transcription after being translocated into the nucleus by binding to ERSE (Yoshida et al. 2000, 2001b). ATF6α(N) is more active than ATF6β(N) as a transcription factor (Haze et al. 2001). In addition, the ATF6α(N)-XBP1(S) heterodimer binds to UPRE with higher affinity than the XBP1(S) homodimer (Fig. 1; Yamamoto et al. 2007).

The major ER chaperone BiP appears to function as an anchor protein for ATF6 under normal conditions (Shen et al. 2002); in my opinion, however, a putative protein that escorts ATF6 from the ER to the Golgi apparatus in response to ER stress has yet to be identified.

CHANGES THAT HAVE OCCURRED IN THE COURSE OF EVOLUTION

Change 1: Advent of PERK in Metazoans

Unicellular yeast expresses only a single sensor/transducer (IRE1) that activates the transcription factor HAC1 upon ER stress but cannot block translation. The cell therefore continues synthesizing proteins even under ER stress. Accordingly, yeast must induce the transcription of ∼6% of its total genes to decrease misfolded proteins in the ER (Travers et al. 2000). The advent of PERK has enabled multicellular organisms to stop translation in response to ER stress (Fig. 2). As new organs have evolved, each with its own function and consequent inability to escape the ER-stressed environment, multicellular organisms may have had to find additional ways to cope with ER stress apart from the IRE1 pathway. Thanks to PERK-mediated translational control, metazoans can decrease ER stress promptly and transiently. Moreover, during this time, the IRE1-mediated transcriptional program can initiate maintenance of ER homeostasis.

Change 2: Switch in Transcription Factor Downstream of IRE1 in Metazoans

The transcription factor downstream of IRE1 is HAC1 in yeast and XBP1 in metazoans (Fig. 2). Although they share limited similarity in amino acid sequences, they are both bZIP-type proteins and their expression is regulated by IRE1-mediated unconventional mRNA splicing. A major difference in regulation between HAC1 and XBP1 is the length of their introns. Unspliced HAC1 mRNA contains an intron comprising 252 nucleotides that can block translation via long-range base pairing between nucleotides present in a stem-loop structure within the intron and other nucleotides in the 5′ untranslated region. This base pairing diminishes the loading of ribosomes onto the cytoplasmic pool of unspliced HAC1 mRNA (Rüegsegger et al. 2001). Therefore, unspliced HAC1 mRNA is not translated under normal conditions. In contrast, unspliced XBP1 mRNA contains an intron comprising 26 nucleotides, which is too short to block translation; unspliced XBP1 mRNA is therefore constitutively translated to produce XBP1(U), as mentioned above.

One possible explanation for the switch from HAC1 to XBP1 in metazoans is that the HAC1 intron-mediated translational block is not compatible with PERK-mediated translational control, which remains to be demonstrated experimentally.

Change 3: Switch in Regulator of ER Chaperone Induction in Vertebrates

Transcriptional induction of ER chaperone genes is mediated by the IRE1-HAC1 pathway in yeast (Cox et al. 1993; Mori et al. 1993) and the IRE1-XBP1 pathway in invertebrates, such as worm (Shen et al. 2001) and fly (Hollien and Weissman 2006). In contrast, the ATF6 pathway mediates ER chaperone induction in vertebrates, such as medaka (Ishikawa et al. 2013) and mice (Fig. 2; Yamamoto et al. 2007). The active form of ATF6, ATF6(N), is produced by ER stress-induced cleavage of a preexisting precursor protein, ATF6(P), whereas the active form of XBP1, XBP1(S), is produced by IRE1-mediated splicing of XBP1 mRNA followed by translation of spliced XBP1 mRNA. ATF6 activation is therefore faster than XBP1 activation. ATF6(N) and XBP1(S) have been detected in HeLa cells from 1 h and 4 h, respectively, after thapsigargin treatment and from 2 h and 4 h, respectively, after tunicamycin treatment (Yoshida et al. 2001a). This suggests that vertebrates require faster induction of ER chaperones. To find the reason for the switch from XBP1 to ATF6, the bZIP domain in XBP1 molecule can be swapped with the bZIP domain of ATF6. The phenotype of ATF6α/ATF6β double-knockout medaka following the introduction of a more slowly activatable ATF6-like protein by IRE1-mediated mRNA splicing should be determined.

Change 4: Increase in the Number of ATF6-Like Local Factors in Vertebrates

Invertebrates express two ATF6-like ER membrane-bound transcription factors, namely, CREB/ ATF-a and CREB/ATF-b; vertebrates, however, express five, namely, OASIS/CREB3L1, BBF2H7/ CREB3L2, Luman/LZIP/CREB3, CREB-H/CREB3L3, and AIbZIP/Tisp40/CREB3L4 (Fig. 2). These five factors are thought to be activated by ER stress-induced proteolysis in a similar manner to ATF6α and ATF6β. Then, if ER stress is simply the accumulation of unfolded/misfolded proteins in the ER, why are so many UPR sensors/transducers required? Unlike ubiquitously expressed ATF6α and ATF6β, these five factors often show tissue-specific expression and are thought to cope with local ER stress (Asada et al. 2011). BBF2H7 indeed copes with local ER stress (see next section). However, it remains unclear whether the accumulation of a particular kind of protein or proteins activates the four other factors.

PHENOTYPE OF VERTEBRATE KNOCKOUT ANIMALS

I here focus on the phenotypes of vertebrate knockout animals as those of invertebrate knockout animals have been covered before (Mori 2009).

IRE1 Pathway

Knockout of XBP1 in mice causes embryonic lethality by E12.5 due to poor development of the liver, which synthesizes and secretes most proteins found in blood. In addition, as the liver is responsible for hematopoiesis during embryonic development, mice with a poorly developed liver suffer from anemia and die (Reimold et al. 2000). When XBP1 is knocked out only in immune cells, B cells become unable to differentiate into plasma cells (Reimold et al. 2001), which synthesize and secrete large amounts of immunoglobulin. Notably, expression of the IgM heavy chain, µs, in HeLa cells using a drug-inducible system at a physiological level resulted in detection of spliced XBP1 mRNA and the cleaved form of ATF6α (Bakunts et al. 2017). Thus, synthesis of large amounts of immunoglobulin is the cause of physiological ER stress in plasma cells.

XBP1-knockout medaka exhibit three defects during embryonic development, namely, a short tail, which synthesizes and secretes large amounts of extracellular matrix proteins, failure of liver development, and failure of hatching gland development, which synthesizes and secretes large amounts of hatching enzymes (proteases). XBP1-knockout medaka therefore cannot hatch (Ishikawa et al. 2017a). These findings indicate that the IRE1-XBP1 pathway is critical to the maintenance of organs that produce large amounts of secretory proteins. This notion is supported by the finding that XBP1 regulates a diverse set of genes ranging from those involved in protein folding and ERAD to those involved in trafficking and secretion or ER to Golgi vesicle-mediated transport to decrease the amounts of unfolded and misfolded proteins in the ER (Acosta-Alvear et al. 2007).

PERK Pathway

PERK-knockout mice develop diabetes mellitus after birth (Harding et al. 2001) because the homeostasis of insulin-producing pancreatic β cells depends on PERK-mediated translational control. β-cell-specific IRE1α conditional knockout mice also show typical diabetic phenotypes that are mild compared with those of PERK-knockout mice (Tsuchiya et al. 2018). I speculate that since proinsulin, a major product of β cells, is a small molecule with a molecular weight under 10 kDa, the induction of genes encoding ER chaperones and other proteins is not effective at refolding of misfolded proinsulin in the ER. Various induced ER chaperones and others would end up competing for small proinsulin. PERK-mediated translational control is more efficient; PERK activated by misfolded proinsulin stops translation and allows endogenous ER chaperones to refold misfolded proinsulin. After misfolded proinsulin is fully refolded, translation restarts via PERK inactivation.

PERK-knockout medaka show no obvious phenotype (our unpublished data) as it is difficult to measure blood glucose level in medaka in our hands.

ATF6 Pathway

ATF6α and ATF6β single-knockout mice show no obvious phenotype (Wu et al. 2007; Yamamoto et al. 2007), whereas ATF6α/ATF6β double-knockout causes embryonic lethality. As we could not obtain E8.5 double-knockout embryos, we cannot determine the cause of embryonic lethality in mice (Yamamoto et al. 2007).

As with mice, ATF6α and ATF6β single-knockout medaka show no obvious phenotype while ATF6α/ATF6β double-knockout causes embryonic lethality (Ishikawa et al. 2013). A fluorescent EGFP reporter under the control of the major ER chaperone BiP promoter was used to detect physiological ER stress in the brain, otic vesicle, and notochord. As the neural tube next to the notochord did not demonstrate physiological ER stress, structural proteins such as extracellular matrix proteins were sought, revealing that knockdown of type VIII collagen expression decreases the physiological ER stress observed in the otic vesicle and notochord. Various ER chaperones are known to assist the productive folding of collagen molecules (Chessler and Byers 1993; Ferreira et al. 1994; Wilson et al. 1998). Notably, only 30 of more than 14,000 mouse genes were found to be ATF6α targets, including seven ER chaperones, five ERAD components, and six ER proteins but not any proteins involved in transport or translocation. This finding in turn has led to the proposal that ATF6 is a transcription factor that is specialized for regulating ER quality control proteins (Adachi et al. 2008). Thus, ATF6-mediated induction of ER chaperones is essential to the quality control of type VIII collagen, which allows the smooth alignment of disk-like notochord cells (see wild-type [WT] in Fig. 4, top left) and progressive expression of Brachyury mRNA, a notochord marker, until the tip of the tail (Ishikawa et al. 2013). In ATF6α/ATF6β double-knockout medaka, the notochord cell structure becomes irregular (see ATF6α/β double-knockout in Fig. 4, top left) and progressive expression of Brachyury mRNA stops in the middle of the tail, leading to death (Ishikawa et al. 2013).

Figure 4.

Figure 4.

Open in a new tab

Phenotypes of ATF6α/ATF6β double-knockout medaka and BBF2H7-kockout medaka.

ATF6-Like BBF2H7 Pathway

BBF2H7 is among the five ATF6-like ER membrane-bound transcription factors present in vertebrates and undergoes ER stress-induced cleavage by S1P and S2P (Fig. 2; Kondo et al. 2007). BBF2H7-knockout mice show severe chondrodysplasia and die by suffocation shortly after birth because of an immature chest cavity. Proliferating chondrocytes show an abnormally expanded ER containing aggregated type II collagen and cartilage oligomeric matrix protein (Saito et al. 2009a).

BBF2H7-knockout medaka develop a flattened head and short tail, and die within 60 d post-hatch (Ishikawa et al. 2017b). As ATF6α and ATF6β are functional in BBF2H7-knockout medaka, notochord cells are smoothly aligned. Problems occur subsequently when notochord cells undergo vacuolization, a differentiation process (Figs. 4 and 5). During vacuolization, notochord cells differentiate into two types of cells. The first type is large vacuolated structural cells in which the vacuoles play a structural role in generating turgor in the notochord. The second type is thin nonvacuolated epithelial cells (sheath cells), which, upon receipt of Mib-Jag1-Notch signaling, start synthesizing type II collagen. Type II collagen synthesis, in turn, leads to the formation of a basement membrane that forms a sheath around the notochord (see WT in Fig. 4, top right; red shows immunostaining of type II collagen). At this stage, the notochord shows bending in BBF2H7 knockout medaka (see BBF2H7-knockout in Fig. 4, top right). Interestingly, ATF6α/BBF2H7 double-knockout medaka show more extensive bending during vacuolization than BBF2H7-knockout medaka. These results suggest that the smooth alignment step with synthesis of type VIII collagen is dependent on ATF6α/ATF6β, whereas the vacuolization step with synthesis of type II collagen is dependent on both ATF6 and BBF2H7.

Figure 5.

Figure 5.

Open in a new tab

Differentiation of the notochord and difference between type VIII and type II collagen.

A major difference between type VIII and type II collagen is their length (Fig. 5). Type II collagen is ∼1500 residues long and contains 360 contiguous tripeptide repeats (Gly-X-Y, where X and Y can be any amino acid) indicated by yellow and green in Figure 5. In contrast, type VIII collagen is a short-chain collagen of only about half the size of type II collagen (∼700 residues). Additionally, because type VIII collagen has multiple breaks comprising two amino acids shown in purple within its 145 repeats of the tripeptide Gly-X-Y, it can be folded into a compact structure with assistance from ER chaperones induced by ATF6. Type VIII collagen can therefore be incorporated into standard COPII vesicles (60–80 nm in diameter) for export from the ER (Fig. 4, bottom left). In contrast, the long rod-like structure (300–400 nm diameter) of type II collagen prevents its incorporation into standard COPII vesicles. COPII vesicles must instead be enlarged to accommodate type II collagen for export from the ER (Fig. 4, bottom right; Malhotra and Erlmann 2015).

COPII vesicles are covered by two protein layers, namely, an inner coat consisting of Sec23 and Sec24 (composed of Sec23a, Sec23b, Sec24a, Sec24b, Sec24c, and Sec24d in vertebrates) and an outer coat consisting of Sec13 and Sec31 (composed of Sec13 alone, Sec31a, and Sec31b in vertebrates) (Fig. 4, bottom). Recently, the key mechanism explaining the enlargement of COPII vesicles to accommodate long-chain collagen was elucidated. Tango1 delays the formation of the outer coat layer by simultaneously binding to long-chain collagen (via binding to the collagen-specific molecular chaperone Hsp47), and Sec23/Sec24 proteins of the inner coat layer. This binding occurs via the SH3 domain present at the amino terminus of Tango1 and the proline-rich domain present at its carboxyl terminus, respectively, allowing vesicle enlargement (Saito et al. 2009b). Tango1-like proteins containing the proline-rich domain but lacking the SH3 domain, such as cTAGE5, form heterodimers with Tango1, which also helps delays the formation of the outer coat layer (Saito et al. 2011).

BBF2H7 has been shown to regulate a set of genes required for COPII vesicle enlargement, namely, Sec23a, Sec24d, Sec13, Sec31a, and Tango1 (Ishikawa et al. 2017b). BBF2H7 thereby enables the transport of type II collagen from the ER to the Golgi apparatus during the vacuolization step (Fig. 4, bottom right). In BBF2H7-knockout medaka, type II collagen is not secreted but is instead retained in the ER (see BBF2H7-knockout in Fig. 4, top right; immunostaining of type II collagen shows red punctate), which causes bending.

REGULATED IRE1-DEPENDENT DECAY OF mRNAs

IRE1 functions independently of XBP1 in two ways (Fig. 3). First, the adaptor molecule TRAF2 binds to activated and phosphorylated IRE1 and sequentially activates ASK1 (MEKK1), JNKK, and JNK, leading to phosphorylation and activation of c-Jun (the JNK pathway) (Urano et al. 2000). Second, activated IRE1 cleaves various mRNAs in a relatively nonspecific manner, a process called regulated IRE1-dependent decay of mRNAs (the RIDD pathway). Both are considered proapoptotic (Urano et al. 2000; Han et al. 2009).

The RIDD pathway was originally discovered in fly S2 cells (Hollien and Weissman 2006) and subsequently in mammalian cells (Hollien et al. 2009). Interestingly, IRE1 in the budding yeast, Saccharomyces cerevisiae, lacks RIDD activity and therefore copes with ER stress by carrying out nonconventional splicing of HAC1 mRNA only. In contrast, IRE1 in the fission yeast, Schizosaccharomyces pombe, has RIDD activity but cannot carry out nonconventional splicing of HAC1 mRNA when introduced into S. cerevisiae (Li et al. 2018). Indeed, as HAC1-like transcription factor is not found in S. pombe, IRE1 in S. pombe copes with ER stress by exhibiting RIDD activity (Kimmig et al. 2012). A recent report revealed the importance of the width of the interfacial area in the RNase dimer (formed by two protomers), which is stabilized by salt bridges, to substrate specificity, since the change of only two amino acids in the RNase domain converted S. cerevisiae IRE1 to S. pombe–type IRE1 (Li et al. 2021). However, despite extensive efforts by many laboratories, how the distinction between the IRE1-XBP1 pathway and IRE1-RIDD pathway is made remains unknown.

The requirement of the IRE1 branch for coping with the physiological ER stress that occurs during embryonic development in the fly has been investigated. Physiological ER stress-dependent strong fluorescent reporter expression observed in XBP1-knockout fly was fully rescued by transgenic expression of the spliced form of XBP1 but that in IRE1-knockout fly was not, indicating that IRE1-mediated signaling independent of XBP1 mRNA splicing, particularly RIDD, is functionally important in this organism (Huang et al. 2017).

In contrast to the fly, the three defects observed in IRE1α/IRE1β double-knockout medaka, namely a short tail, failure of liver development, and failure of hatching gland development, were fully rescued by constitutive activation of XBP1 via genome editing–mediated deletion of its intron. Thus, XBP1 mRNA splicing–mediated production of XBP1(S) was sufficient to cope with the physiological ER stress that occurs during normal growth and development of medaka (Ishikawa et al. 2017a). The advent of functional ATF6 has been proposed to mitigate the importance of RIDD in vertebrates, because ATF6-mediated rapid induction of various ER chaperones to help refold unfolded and misfolded proteins appears to be a more sophisticated way of coping with ER stress than the relatively nonspecific RIDD-mediated degradation of various mRNAs, from which no functional proteins could be produced.

Although knocking out XBP1 causes embryonic lethality in mice due to the failure of liver development (Reimold et al. 2000) as mentioned above, liver-specific conditional XBP1-knockout in adult mice has almost no effect on either their growth or on protein secretion from their hepatocytes (Lee et al. 2008). This lack of difference is probably due to compensation by the ATF6 pathway, which is responsible for transcriptional induction of ER chaperone genes in response to ER stress in both mice and medaka, although not in invertebrates (Yamamoto et al. 2007; Ishikawa et al. 2013). Interestingly, liver-specific conditional XBP1-knockout mice showed hypolipidemia and XBP1 was found to regulate transcription of noncanonical UPR target genes that encode four enzymes involved in lipidogenesis (Lee et al. 2008). Furthermore, the absence of XBP1 from mouse liver leads to IRE1α hyperactivation, and hypolipidemia is accordingly accelerated by RIDD of mRNAs encoding proteins involved in lipogenesis and lipoprotein metabolism (So et al. 2012). However, note that IRE1α hyperactivation does not always induce RIDD; the deletion of XBP1 from mouse cartilage leads to IRE1α hyperactivation in chondrocytes, which is not sufficient for activation of RIDD, unlike the liver (Cameron et al. 2015).

Based on these results, the protein quality control system is thought to be maintained by the IRE1-XBP1 and ATF6 branches of the UPR and not by the RIDD pathway at the whole-body level in mice and medaka. The RIDD pathway may have more specific functions in vertebrates, for example, the regulation of lipid metabolism in collaboration with the noncanonical function of XBP1, as mentioned above; and protection against toxins such as acetaminophen and cholera toxin. RIDD blocks acetaminophen-induced hepatotoxicity by degrading Cyp1a2 and Cyp2e1 mRNAs, whose translational products convert acetaminophen to hepatotoxic metabolites in adult mice with liver specific-conditional XBP1-knockout (Hur et al. 2012), while cholera toxin induces an inflammatory response via RIDD-mediated production of mRNA fragments that activate retinoic-acid-inducible gene 1 (RIG1). RIG1 activation leads, in turn, to activation of NF-κB and interferon (Cho et al. 2013). Further, Japanese encephalitis virus–induced and RIDD-mediated degradation of endogenous mRNAs in mouse neuroblastoma cells benefits viral replication (Bhattacharyya et al. 2014). It is important to differentiate the activities of the protein quality control system from other events that occur in the ER in vertebrates.

CONCLUDING REMARKS

The identification of UPR mediators and clarification of the UPR's basic molecular mechanism in various organisms have provided the opportunity to consider the evolutionary aspects of the UPR, leading to unraveling the four major changes that have occurred in the course of evolution. They also have led to phenotypic analysis of invertebrate and vertebrate knockout animals. Recent advances in the analysis of physiological ER stress in knockout animals have improved our understanding of what happens in specific organs of a knockout animal, namely, what is the problem and how is it overcome in WT animals. Notably, the UPR not only copes with the accumulation of unfolded and misfolded proteins in the ER but also deals with the emergence of long cargo proteins that cannot be incorporated into standard COPII vesicles.

Conducting the experiments described in the section “Changes that Have Occurred in the Course of Evolution” will further enhance our understanding of how the UPR has evolved to adjust to new environments/situations and how sophisticated the UPR has become in its maintenance of ER homeostasis.

COMPETING INTEREST STATEMENT

The author declares no competing financial interests.

Footnotes

Editors: Susan Ferro-Novick, Tom A. Rapoport, and Randy Schekman

Additional Perspectives on The Endoplasmic Reticulum available at www.cshperspectives.org

REFERENCES

  1. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD. 2007. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27: 53–66. 10.1016/j.molcel.2007.06.011 [DOI] [PubMed] [Google Scholar]
  2. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. 2008. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct 33: 75–89. 10.1247/csf.07044 [DOI] [PubMed] [Google Scholar]
  3. Asada R, Kanemoto S, Kondo S, Saito A, Imaizumi K. 2011. The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J Biochem 149: 507–518. 10.1093/jb/mvr041 [DOI] [PubMed] [Google Scholar]
  4. Bakunts A, Orsi A, Vitale M, Cattaneo A, Lari F, Tadè L, Sitia R, Raimondi A, Bachi A, van Anken E. 2017. Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude. eLife 6: e27518. 10.7554/eLife.27518 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bhattacharyya S, Sen U, Vrati S. 2014. Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication. J Gen Virol 95: 71–79. 10.1099/vir.0.057265-0 [DOI] [PubMed] [Google Scholar]
  6. Bukau B, Weissman J, Horwich A. 2006. Molecular chaperones and protein quality control. Cell 125: 443–451. 10.1016/j.cell.2006.04.014 [DOI] [PubMed] [Google Scholar]
  7. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D. 2002. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92–96. 10.1038/415092a [DOI] [PubMed] [Google Scholar]
  8. Cameron TL, Gresshoff IL, Bell KM, Piróg KA, Sampurno L, Hartley CL, Sanford EM, Wilson R, Ermann J, Boot-Handford RP, et al. 2015. Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization. Osteoarthritis Cartilage 23: 661–670. 10.1016/j.joca.2015.01.001 [DOI] [PubMed] [Google Scholar]
  9. Chessler SD, Byers PH. 1993. Bip binds type I procollagen pro α chains with mutations in the carboxyl-terminal propeptide synthesized by cells from patients with osteogenesis imperfecta. J Biol Chem 268: 18226–18233. 10.1016/S0021-9258(17)46834-7 [DOI] [PubMed] [Google Scholar]
  10. Cho JA, Lee AH, Platzer B, Cross BC, Gardner BM, De Luca H, Luong P, Harding HP, Glimcher LH, Walter P, et al. 2013. The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13: 558–569. 10.1016/j.chom.2013.03.011. Retraction in: Cell Host Microbe 2018. Apr 11; 23(4): 571. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  11. Cox JS, Shamu CE, Walter P. 1993. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73: 1197–1206. 10.1016/0092-8674(93)90648-A [DOI] [PubMed] [Google Scholar]
  12. Ferreira LR, Norris K, Smith T, Hebert C, Sauk JJ. 1994. Association of Hsp47, Grp78, and Grp94 with procollagen supports the successive or coupled action of molecular chaperones. J Cell Biochem 56: 518–526. 10.1002/jcb.240560412 [DOI] [PubMed] [Google Scholar]
  13. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR. 2009. IRE1α kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138: 562–575. 10.1016/j.cell.2009.07.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harding HP, Zhang Y, Ron D. 1999. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397: 271–274. 10.1038/16729 [DOI] [PubMed] [Google Scholar]
  15. Harding HP, Novoa II, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. 2000. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6: 1099–1108. 10.1016/S1097-2765(00)00108-8 [DOI] [PubMed] [Google Scholar]
  16. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D. 2001. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7: 1153–1163. 10.1016/S1097-2765(01)00264-7 [DOI] [PubMed] [Google Scholar]
  17. Harding HP, Calfon M, Urano F, Novoa I, Ron D. 2002. Transcriptional and translational control in the mammalian unfolded protein response. Annu Rev Cell Dev Biol 18: 575–599. 10.1146/annurev.cellbio.18.011402.160624 [DOI] [PubMed] [Google Scholar]
  18. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, et al. 2003. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619–633. 10.1016/S1097-2765(03)00105-9 [DOI] [PubMed] [Google Scholar]
  19. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. 1999. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10: 3787–3799. 10.1091/mbc.10.11.3787 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Haze K, Okada T, Yoshida H, Yanagi H, Yura T, Negishi M, Mori K. 2001. Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem J 355: 19–28. 10.1042/bj3550019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hollien J, Weissman JS. 2006. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313: 104–107. 10.1126/science.1129631 [DOI] [PubMed] [Google Scholar]
  22. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. 2009. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186: 323–331. 10.1083/jcb.200903014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Huang HW, Zeng X, Rhim T, Ron D, Ryoo HD. 2017. The requirement of IRE1-XBP1 in resolving physiological stress during Drosophila development. J Cell Sci 130: 3040–3049. 10.1242/jcs.203612 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH. 2012. IRE1α activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 209: 307–318. 10.1084/jem.20111298 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ishikawa T, Taniguchi Y, Okada T, Takeda S, Mori K. 2011. Vertebrate unfolded protein response: mammalian signaling pathways are conserved in medaka fish. Cell Struct Funct 36: 247–259. 10.1247/csf.11036 [DOI] [PubMed] [Google Scholar]
  26. Ishikawa T, Okada T, Ishikawa-Fujiwara T, Todo T, Kamei Y, Shigenobu S, Tanaka M, Saito TL, Yoshimura J, Morishita S, et al. 2013. ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish. Mol Biol Cell 24: 1387–1395. 10.1091/mbc.e12-11-0830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ishikawa T, Kashima M, Nagano AJ, Ishikawa-Fujiwara T, Kamei Y, Todo T, Mori K. 2017a. Unfolded protein response transducer IRE1-mediated signaling independent of XBP1 mRNA splicing is not required for growth and development of medaka fish. eLife 6: e26845. 10.7554/eLife.26845 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ishikawa T, Toyama T, Nakamura Y, Tamada K, Shimizu H, Ninagawa S, Okada T, Kamei Y, Ishikawa-Fujiwara T, Todo T, et al. 2017b. UPR transducer BBF2H7 allows export of type II collagen in a cargo- and developmental stage–specific manner. J Cell Biol 216: 1761–1774. 10.1083/jcb.201609100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kimmig P, Diaz M, Zheng J, Williams CC, Lang A, Aragón T, Li H, Walter P. 2012. The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis. eLife 1: e00048. 10.7554/eLife.00048 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kondo S, Saito A, Hino S, Murakami T, Ogata M, Kanemoto S, Nara S, Yamashita A, Yoshinaga K, Hara H, et al. 2007. BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer. Mol Cell Biol 27: 1716–1729. 10.1128/MCB.01552-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J. 1988. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332: 462–464. 10.1038/332462a0 [DOI] [PubMed] [Google Scholar]
  32. Lee AH, Scapa EF, Cohen DE, Glimcher LH. 2008. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320: 1492–1496. 10.1126/science.1158042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Li W, Okreglak V, Peschek J, Kimmig P, Zubradt M, Weissman JS, Walter P. 2018. Engineering ER-stress dependent non-conventional mRNA splicing. eLife 7: e35388. 10.7554/eLife.35388 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Li W, Crotty K, Garrido Ruiz D, Voorhies M, Rivera C, Sil A, Mullins RD, Jacobson MP, Peschek J, Walter P. 2021. Protomer alignment modulates specificity of RNA substrate recognition by Ire1. eLife 10: e67425. 10.7554/eLife.67425 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Malhotra V, Erlmann P. 2015. The pathway of collagen secretion. Annu Rev Cell Dev Biol 31: 109–124. 10.1146/annurev-cellbio-100913-013002 [DOI] [PubMed] [Google Scholar]
  36. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. 2004. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18: 3066–3077. 10.1101/gad.1250704 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mori K. 2000. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451–454. 10.1016/S0092-8674(00)80855-7 [DOI] [PubMed] [Google Scholar]
  38. Mori K. 2009. Signalling pathways in the unfolded protein response: development from yeast to mammals. J Biochem 146: 743–750. 10.1093/jb/mvp166 [DOI] [PubMed] [Google Scholar]
  39. Mori K, Ma W, Gething MJ, Sambrook J. 1993. A transmembrane protein with a cdc2+CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell 74: 743–756. 10.1016/0092-8674(93)90521-Q [DOI] [PubMed] [Google Scholar]
  40. Nadanaka S, Yoshida H, Kano F, Murata M, Mori K. 2004. Activation of mammalian unfolded protein response is compatible with the quality control system operating in the endoplasmic reticulum. Mol Biol Cell 15: 2537–2548. 10.1091/mbc.e03-09-0693 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ninagawa S, George G, Mori K. 2021. Mechanisms of productive folding and endoplasmic reticulum-associated degradation of glycoproteins and non-glycoproteins. Biochim Biophys Acta Gen Subj 1865: 129812. 10.1016/j.bbagen.2020.129812 [DOI] [PubMed] [Google Scholar]
  42. Novoa I, Zeng H, Harding HP, Ron D. 2001. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2a. J Cell Biol 153: 1011–1022. 10.1083/jcb.153.5.1011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Reimold AM, Etkin A, Clauss I, Perkins A, Friend DS, Zhang J, Horton HF, Scott A, Orkin SH, Byrne MC, et al. 2000. An essential role in liver development for transcription factor XBP-1. Genes Dev 14: 152–157. 10.1101/gad.14.2.152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH. 2001. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412: 300–307. 10.1038/35085509 [DOI] [PubMed] [Google Scholar]
  45. Ron D, Walter P. 2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519–529. 10.1038/nrm2199 [DOI] [PubMed] [Google Scholar]
  46. Rüegsegger U, Leber JH, Walter P. 2001. Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response. Cell 107: 103–114. 10.1016/S0092-8674(01)00505-0 [DOI] [PubMed] [Google Scholar]
  47. Saito A, Hino S, Murakami T, Kanemoto S, Kondo S, Saitoh M, Nishimura R, Yoneda T, Furuichi T, Ikegawa S, et al. 2009a. Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nat Cell Biol 11: 1197–1204. 10.1038/ncb1962 [DOI] [PubMed] [Google Scholar]
  48. Saito K, Chen M, Bard F, Chen S, Zhou H, Woodley D, Polischuk R, Schekman R, Malhotra V. 2009b. TANGO1 facilitates cargo loading at endoplasmic reticulum exit sites. Cell 136: 891–902. 10.1016/j.cell.2008.12.025 [DOI] [PubMed] [Google Scholar]
  49. Saito K, Yamashiro K, Ichikawa Y, Erlmann P, Kontani K, Malhotra V, Katada T. 2011. cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites. Mol Biol Cell 22: 2301–2308. 10.1091/mbc.e11-02-0143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shen X, Ellis RE, Lee K, Liu CY, Yang K, Solomon A, Yoshida H, Morimoto R, Kurnit DM, Mori K, et al. 2001. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107: 893–903. 10.1016/S0092-8674(01)00612-2 [DOI] [PubMed] [Google Scholar]
  51. Shen J, Chen X, Hendershot L, Prywes R. 2002. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3: 99–111. 10.1016/S1534-5807(02)00203-4 [DOI] [PubMed] [Google Scholar]
  52. Shen X, Ellis RE, Sakaki K, Kaufman RJ. 2005. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet 1: e37. 10.1371/journal.pgen.0010037 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, et al. 2012. Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 16: 487–499. 10.1016/j.cmet.2012.09.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tirasophon W, Welihinda AA, Kaufman RJ. 1998. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12: 1812–1824. 10.1101/gad.12.12.1812 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P. 2000. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101: 249–258. 10.1016/S0092-8674(00)80835-1 [DOI] [PubMed] [Google Scholar]
  56. Tsuchiya Y, Saito M, Kadokura H, Miyazaki JI, Tashiro F, Imagawa Y, Iwawaki T, Kohno K. 2018. IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells. J Cell Biol 217: 1287–1301. 10.1083/jcb.201707143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. 2000. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664–666. 10.1126/science.287.5453.664 [DOI] [PubMed] [Google Scholar]
  58. Walter P, Ron D. 2011. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334: 1081–1086. 10.1126/science.1209038 [DOI] [PubMed] [Google Scholar]
  59. Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D. 1998. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17: 5708–5717. 10.1093/emboj/17.19.5708 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R. 2000. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 275: 27013–27020. 10.1016/S0021-9258(19)61473-0 [DOI] [PubMed] [Google Scholar]
  61. Wilson R, Lees JF, Bulleid NJ. 1998. Protein disulfide isomerase acts as a molecular chaperone during the assembly of procollagen. J Biol Chem 273: 9637–9643. 10.1074/jbc.273.16.9637 [DOI] [PubMed] [Google Scholar]
  62. Wu X, Rapoport TA. 2018. Mechanistic insights into ER-associated protein degradation. Curr Opin Cell Biol 53: 22–28. 10.1016/j.ceb.2018.04.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ. 2007. ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13: 351–364. 10.1016/j.devcel.2007.07.005 [DOI] [PubMed] [Google Scholar]
  64. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K. 2007. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev Cell 13: 365–376. 10.1016/j.devcel.2007.07.018 [DOI] [PubMed] [Google Scholar]
  65. Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, Brown MS, Goldstein JL. 2000. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6: 1355–1364. 10.1016/S1097-2765(00)00133-7 [DOI] [PubMed] [Google Scholar]
  66. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. 1998. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins; involvement of basic-leucine zipper transcription factors. J Biol Chem 273: 33741–33749. 10.1074/jbc.273.50.33741 [DOI] [PubMed] [Google Scholar]
  67. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K. 2000. ATF6 activated by proteolysis directly binds in the presence of NF-Y (CBF) to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 20: 6755–6767. 10.1128/MCB.20.18.6755-6767.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. 2001a. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881–891. 10.1016/S0092-8674(01)00611-0 [DOI] [PubMed] [Google Scholar]
  69. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K. 2001b. Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6α and 6β that activates the mammalian unfolded protein response. Mol Cell Biol 21: 1239–1248. 10.1128/MCB.21.4.1239-1248.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Yoshida H, Oku M, Suzuki M, Mori K. 2006. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol 172: 565–575. 10.1083/jcb.200508145 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Yoshida H, Uemura A, Mori K. 2009. pXBP1(U), a negative regulator of the unfolded protein response activator pXBP1(S), targets ATF6 but not ATF4 in proteasome-mediated degradation. Cell Struct Funct 34: 1–10. 10.1247/csf.06028 [DOI] [PubMed] [Google Scholar]

Articles from Cold Spring Harbor Perspectives in Biology are provided here courtesy of Cold Spring Harbor Laboratory Press

RESOURCES