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Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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ire1 HAC1u strain using cDNA microarray technology. Comparison of the gene expression profile was also performed between non-stressed wild-type cells and those exposed to ER stress. Genes for which the expression level was significantly changed in both of these experiments were categorized as targets of the Ire1-HAC1 signaling pathway. This analysis revealed that in addition to the previously known UPR targets, some anti-oxidative stress genes were up-regulated by the Ire1-HAC1 pathway, possibly in order to reduce reactive oxygen species produced during the cellular response to ER stress. Moreover, we categorized 15 genes as those down-regulated by the UPR, most of which seem to encode cell surface or extracellular proteins. This UPR-mediated gene repression may alleviate the load of client proteins targeted to the ER. |
Introduction |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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ER-resident molecular chaperone and protein-folding catalyst genes are classically known targets of this Ire1-HAC1 signaling pathway. These genes possess a promoter element termed the UPR element (Mori et al. 1992; Kohno et al. 1993; Mori et al. 1998), and the Hac1i protein binds directly to this element for transcriptional induction (Mori et al. 1996). More recently, Travers et al. (2000) performed gene expression profiling using cDNA microarray technology, and picked up genes that were induced by both of the potent ER stressors dithiothreitol (DTT) and tunicamycin only in IRE1 HAC1 cells. Their analysis yielded more than 300 novel UPR target genes including those involved in ER-associated degradation (ERAD), intracellular vesicle transport and lipid biosynthesis.
Downstream events stimulated by ER stress seem more complicated and divergent in mammalian cells. Transcription factor ATF6, which induces genes encoding ER-resident chaperones and folding catalysts, is synthesized as a transmembrane protein and activated by proteolysis in response to ER stress (Haze et al. 1999). Another signaling cascade that resembles the yeast Ire1-HAC1 pathway is also present. Mammalian cells have two Ire1 paralogues, Ire1
and Ire1ß (Tirasophon et al. 1998; Wang et al. 1998; Iwawaki et al. 2001), which promote splicing of XBP1 premRNA to yield mature mRNA (Yoshida et al. 2001; Calfon et al. 2002). The transcription factor protein produced from this mRNA is highly active in inducing various genes to alleviate ER stress. Moreover, ER stress attenuates bulk protein synthesis. This is caused by phosphorylation of the eukaryotic translation initiation factor 2 alpha subunit (eIF2) by PKR-like ER kinase (PERK) and by cleavage of 28S rRNA by Ire1ß (Harding et al. 1999; Iwawaki et al. 2001). Intriguingly, the phosphorylation of eIF2 stimulates translation of the ATF4 mRNA (Harding et al. 2000), which carries a unique structure at the 5' untranslated region, and the resulting transcription factor protein also induces various genes including those encoding anti-oxidative stress proteins (Harding et al. 2003).
In the present study, we performed genome-wide expression profiling of a yeast strain in which the UPR pathway was constitutively activated by a mutation of the HAC1 gene to the HAC1i sequence. Expression changes resulting from treatment of wild-type cells with tunicamycin were also examined. These analyses yielded novel target genes of the Ire1-HAC1 pathway, which implies new physiological aspects of the yeast UPR.
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Results |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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At the beginning of this study, we generated a yeast strain in which the chromosomal HAC1 gene was mutated to HAC1i that does not contain the intron sequence. As illustrated in Fig. 1A, a method named transplacement (Lundblad 1994) was used for this mutagenesis. The ire1 HAC1 strain Y11907
[GenBank]
transformed with a URA3 integration plasmid pRS306-partialHAC1i was streaked on agar-solidified medium containing 5-fluoroorotic acid (5-FOA) to counterselect the URA3 marker, and the 5-FOA-resistant colonies were tested for growth on agar-solidified medium containing tunicamycin. This selection yielded 5 tunicamycin-resistant clones, the genotypes of which were deduced to be ire1 HAC1i, together with 25 tunicamycin-sensitive clones. The tunicamycin-sensitive clones were deduced to carry the wild-type HAC1 gene, producing HAC1u mRNA that was not spliced in the ire1 background. Therefore, we hereafter call these clones HAC1i (formally ire1 HAC1i) or HAC1u(formally ire1 HAC1) strains. As shown in the example in Fig. 1B, PCR amplification of genomic DNA indicated that indeed, the HAC1 gene in the HAC1i strains was shorter than that in the HAC1u strains and the parent strain Y11907
[GenBank]
. DNA sequencing of the PCR products confirmed that both the HAC1u and HAC1i strains carried the expected types of the HAC1 gene (data not shown).
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Genome-wide gene expression changes caused by up-regulation of the UPR pathway
In order to perform gene expression profiling, the RNA preparations used in Fig. 1C were used for further analyses. As described in the Experimental procedures section, mRNA was purified from the total RNA preparations and used for synthesis of Cy3 or Cy5 fluorescent dye-labeled cDNA. The Cy3-labeled and Cy5-labeled cDNA probes were mixed and hybridized to whole genome yeast microarrays, and the expression ratio (Cy3 (or Cy5) signal intensity/Cy5 (or Cy3) signal intensity) of each spot was estimated. Here we performed two types of gene expression profiling, the results of which are listed in Supplementary Table S1. First, gene expression of HAC1i cells was compared to that of HAC1u cells. In this analysis, cells were cultured under non-stressed conditions. Second, wild-type cells treated with tunicamycin were compared with those cultured under the non-stressed conditions. In Fig. 2, the results of these two analyses were expressed as a scatter plot, which shows that overall expression changes caused by the HAC1i mutation positively correlated to that by tunicamycin treatment of wild-type cells.
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The 90 genes that we designated as up-regulated by the UPR are listed in Table 1. Among them, 58 genes, including those encoding ER-located chaperones, protein-folding catalysts, ERAD factors and COP II components, were also assigned to the UPR targets in the previous report by Travers et al. (2000). One of the most drastically up-regulated genes was an ER-located cochaperone gene SIL1 (see Supplementary Table S1), and we monitored its expression by Northern blot analysis of total RNA preparations in order to confirm the observations from the microarray analyses. The uppermost panel of Fig. 3A, together with the subsequent image analysis (Fig. 3B), demonstrates that SIL1 expression is highly induced both by the HAC1i mutation and by treatment of wild-type cells with the extrinsic ER stressor tunicamycin or DTT. In contrast, ER stress did not induce SIL1 in ire1 or hac1 cells.
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ire1 or hac1 cells. Northern blotting against the Ty1 transposon sequence indicated that its expression was not affected by activation of the UPR pathway (data not shown). Another novel finding is that some genes acting to protect cells from oxidative stress are up-regulated by the UPR (Table 1). This observation was confirmed by Northern blot detection of TSA1 (Fig. 3A (second panel), B), which encodes a protein acting both as a thioredoxin peroxidase catalyzing reduction of peroxides and as a molecular chaperone following oxidative stress (Jang et al. 2004).
All of the genes that we designated as down-regulated by the UPR are listed in Table 2. Except for ACO1, all of these genes encode proteins that are deduced to carry the N-terminal signal sequence and/or transmembrane domain(s). According to the Yeast Proteome Database (YPD) reports and previously published papers indicated in Table 2, most of the gene products are extracellular or cell surface (plasma membrane, periplasmic space or cell wall) proteins. Down-regulation of individual genes by the UPR was confirmed by Northern blotting (Fig. 3A (fourth to seventh panels) and B for ATO3, ELO1, TIP1 and TPO1). The Hac1i mutation, together with imposition of extrinsic ER stress on wild-type cells, clearly repressed expression of these genes. In contrast, ER stress caused no or only weak repression in ire1 or hac1 cells.
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Some genes acting to protect cells from oxidative stress are up-regulated by the transcription factor Yap1 (Lee et al. 1999). In yeast cells, there is a pathway in which peroxides activate Yap1 (Delaunay et al. 2002). Does the UPR pathway merge with the Yap1 pathway to control oxidative stress-gene expression? In order to answer this question, we monitored TSA1 expression under several conditions (Fig. 4).
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yap1 cells showed sharp induction of TSA1 expression in response to tunicamycin (4.1-fold induction in Fig. 4C). Deletion of the IRE1 gene attenuated the response to tunicamycin but not to H2O2. As shown in Fig. 4C, induction of TSA1 expression by tunicamycin was only 1.6-fold both in ire1 cells and in ire1 yap1 cells. Based on these results, we have made the following conclusions. Induction of TSA1 expression by tunicamycin is mediated by the UPR pathway and probably by another unidentified signaling pathway, not involving the YAP1 pathway. In contrast, induction by H2O2 is mediated only by the YAP1 pathway.
Cellular sensitivity to ER stress is enhanced by expression of a secretory protein from a strong promoter not down-regulated by the UPR
Does the down-regulation of genes encoding extracellular or cell surface proteins contribute resistance of yeast cells to ER stress? In order to answer this question, we expressed a heterogeneous secretory protein, Rhizopus niveus aspartic proteinase-1 (RNAP-1), from the GAL1 promoter in wild-type (IRE1 HAC1) cells. As reported in Horiuchi et al. (1990), RNAP-1 is efficiently secreted from yeast cells. It is well known that the GAL1 promoter is strongly induced when cells are cultured in galactose-based medium, and the expression level from this promoter was hardly changed by the UPR (see Supplementary Table S1).
Cells were cultured in galactose-based medium, exposed to ER stress, and then plated on glucose-based medium plates not containing ER stressors. In the experimental conditions used in Fig. 5, the number of the resulting colonies was affected neither by expression of RNAP-1 nor by exposure to ER stress (data not shown). However, the size of the colonies was significantly affected. To quantify cellular growth on the plates, we harvested cells into PBS, and monitored optical density of the suspensions.
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Discussion |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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ire1 HAC1), in which the Ire1-HAC1 pathway is completely blocked, were mutagenized to carry the HAC1i gene for the constitutive activation of this pathway (Fig. 1), and expression changes caused by this mutation were examined. In order to confirm that the expression change of each gene is reproduced by extrinsic ER stress to wild-type (IRE1 HAC1) cells, we performed the second analysis. Wild-type cells were cultured under the non-stressed conditions or treated with tunicamycin, and the gene expression profiles were compared. The second analysis alone is insufficient because as described in Bonilla et al. (2002) and Schroder et al. (2003), tunicamycin can alter gene expression via other signaling pathways. However, the expression changes indicated in these two analyses seemed to show a relatively high correlation (Fig. 2), and we now think that tunicamycin-induced transcriptional changes in yeast cells are mediated mainly by the Ire1-HAC1 pathway. Based on the criteria described in the Results section, we designated 90 genes as those up-regulated by the UPR (induced in both of the cDNA microarray analyses; Table 1) and 15 genes as those down-regulated by the UPR (repressed in both of the cDNA microarray analyses; Table 2). As shown in Fig. 3, the results of the cDNA microarray analyses were partly confirmed by Northern blot detection of the expression of individual genes. Deletion of either IRE1 or HAC1 attenuated the expression changes caused by DTT. This observation further confirms that these expression changes were mediated by the Ire1-HAC1 pathway.
Although another cDNA microarray analysis to identify UPR target genes was previously reported by Travers et al. (2000), our study identified a series of new genes as novel UPR targets. This is first because our microarrays carried multiple genes not examined in Travers et al. (2000). Moreover, Travers et al. (2000) picked up genes up-regulated by tunicamycin and DTT not in ire1 or hac1 cells but in wild-type cells in their initial cDNA microarray screening. As they mentioned in their report, their criteria were often too severe, so that they initially missed KAR2, which is the most well-known UPR target. It should be noted that weak induction of TSA1 by tunicamycin was observed even in ire1 cells (Fig. 4), which explains why this gene was missed in Travers et al. (2000). Finally, to our knowledge, our present paper is the first report that documents down-regulation of gene expression by the UPR in yeast cells.
Ty1 and Ty2 are the two major transposons found on the S. cerevisiae genome. Here we show that expression of Ty2, but not Ty1 is induced by the Ire1-HAC1 pathway (Table 1, Fig. 3). According to previous reports, Ty2 expression is also controlled by other transcriptional regulator proteins (Turkel & Farabaugh 1993; Turkel et al. 1997; Turkel 2002). The physiological meaning of this regulation is presently unclear.
Sustained ER stress was reported to cause oxidative stress both in yeast and mammalian cells (Harding et al. 2003; Haynes et al. 2004). This seems to be a "side-effect" of cellular responses against ER stress, as oxidative protein folding intensified by loading of client proteins to the ER somehow results in the production of reactive oxygen species (ROS) (Haynes et al. 2004). Therefore, it makes sense that genes involved in cellular protection against oxidative stress are induced by the UPR in yeast cells (Table 1). By which mechanism does the Ire1-HAC1 pathway induce anti-oxidative stress genes? In one scenario, the UPR induces genes that are involved in oxidative protein folding (disulfide bond formation; Table 1), so that ROS are produced. Indeed, deletion of IRE1 is reported to attenuate ROS production by sustained ER stress (Haynes et al. 2004). Then ROS up-regulates the Yap1 pathway, which functions to induce anti-oxidative stress genes. However, this explanation is unlikely at least under the conditions in this study, since the results in Fig. 4 show that Yap1 is not required for TSA1 induction by tunicamycin. Therefore, we believe that ER stress induces anti-oxidative stress genes more directly via the Ire1-HAC1 pathway. It should be noted that ER stress also induces anti-oxidative stress genes in mammalian cells. As reported in Harding et al. (2003), this is mediated by the PERK-ATF4 pathway.
Another finding in this study is that expression of genes encoding extracellular or cell surface proteins is repressed by the Ire1-HAC1 pathway. Just after synthesis, these proteins are known to traverse the ER. Therefore, this transcriptional repression may act to reduce the load of client proteins to the ER and thus alleviate the ER stress. Indeed, the result in Fig. 5 suggests that this repression contributes resistance of yeast cells to ER stress. Also in plant cells, DTT and tunicamycin repress expression of several genes encoding extracellular or cell surface proteins (Martinez & Chrispeels 2003), though it is unclear by which signaling pathway this phenomenon is mediated. To our knowledge, such a phenomenon has not been reported in mammalian cells. Instead, translational repression by PERK and Ire1ß is believed to reduce the load of client proteins under ER-stressed conditions (Harding et al. 1999; Iwawaki et al. 2001). Since yeast cells carry neither PERK nor Ire1ß (yeast Ire1 does not seem to have rRNA cleaving activity), transcriptional repression by the Ire1-HAC1 pathway may be required.
Also, it should be noted that two of the down-regulated genes, FRE1 and FET3, encode iron (and copper) oxidoreductases that are involved in transport of these metal ions. Therefore, the resulting attenuation of oxidoreduction and/or transport of the metal ions may have physiological meanings, for example, reduction of ROS production.
In conclusion, here we identified novel targets of the Ire1-HAC1 pathway, which imply new physiological aspects of the yeast UPR. As described in the Introduction section, intracellular signaling in response to ER stress of yeast seems to be simple in comparison to that of mammals. However, this "simplicity" may be compensated by the "multiplicity" of the final targets of the Ire1-HAC1 pathway. One question left unresolved is by which molecular mechanism the Hac1i protein regulates the novel UPR targets. Unlike results reported by Patil et al. (2004), our preliminary computer search failed to identify consensus promoter elements carried on these genes. In addition, the contribution of other regulator proteins, which was proposed in previous reports (Schroder et al. 2003; Patil et al. 2004), remains obscure. By addressing these problems, together with the findings in this study, we hope that novel aspects of the UPR will be further uncovered both at the physiological and molecular levels.
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Experimental procedures |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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Yeast strains BY4742 (alias Y10000
[GenBank]
), Y10569
[GenBank]
, Y11907
[GenBank]
and Y15650
[GenBank]
were provided by the European Saccharomyces Cerevisiae Archive for Functional analysis (EUROSCARF; Johann Wolfgang Goethe-University Frankfurt, Germany; http://web.uni-frankfurt.de/fb15/mikro/euroscarf/index.html). BY4742 (MAT his31 leu20 lys20 ura30; Brachmann et al. 1998) was used as wild-type, and the other strains were isogenic deletion derivatives (Y10569
[GenBank]
, yap1::KanMX4; Y11907
[GenBank]
, ire1::KanM4; Y15650
[GenBank]
, hac1::KanMX4). Observations obtained from these deletion strains were well reproduced by using strains yielded by retransformation of BY4742 with the KanMX4-containing disruption DNA fragments that had been PCR amplified from the original EUROSCARF strains. To obtain ire1 yap1 strain YKY1003, the IRE1 gene on the chromosome of Y10569
[GenBank]
was replaced to the URA3 gene.
Plasmid pRS306-partialHAC1i was derived from the yeast URA3 integration vector pRS306 (Sikorski & Hieter 1989) by the following procedure. The wild-type HAC1 gene was PCR amplified from BY4742 using a sense primer [5'-GAACAACAACTTATTTTTACAATGA-3'] and an anti-sense primer [5'-ccgagcttgcggccgcAATAGACAGATAGATATGACACAA-3' (the hybridizing sequence is indicated by capital letters, and the attached NotI site is underlined)], and digested at an internal XhoI site and the terminally attached NotI site. The resulting 3' portion of the HAC1 gene was ligated with the XhoI/NotI-digested pRS306, and the intron sequence was deleted using the standard site-directed mutagenesis technique. Transplacement mutagenesis (Lundblad 1994) of Y11907
[GenBank]
using pRS306-partialHAC1i is described in the Results section, and the resulting HAC1u strain (MAT his31 leu20 lys20 ura30 ire1::KanM4 HAC1) and HAC1i strain (MAT his31 leu20 lys20 ura30 ire1::KanM4 HAC1i) were, respectively, named YKY1001 and YKY1002.
Yeast strain KMY1005 (MAT ura3-52 leu2-3112 his3-200 trp1-901 lys2-801) is a generous gift of Kazutoshi Mori (Kyoto University, Kyoto, Japan). Yeast TRP1 centeromeric vector pRS314 is described in Sikorski & Hieter (1989). A YRp plasmid carrying the TRP1 marker and a fusion of the GAL1 promoter and the RNAP-1 cDNA, named pYPR3831, is a generous gift of Dr Masamichi Takagi (The University of Tokyo, Tokyo, Japan).
Yeast techniques
Yeast cells were cultured at 30 °C on SD medium (2% glucose, 0.66% yeast nitrogen base (without amino acids; Difco) and appropriate auxotrophic supplements) solidified with 2% agar or in liquid SC medium (SD medium supplemented with a variety of amino acids and vitamins; Kaiser et al. 1994) or SGC medium (the same composition as SC but containing 2% galactose instead of glucose). 5-FOA, DTT and tunicamycin were, respectively, added to the medium at final concentrations of 0.5 mg/mL, 10 mM and 2 µg/mL. Genetic manipulation was according to Kaiser et al. (1994). Total RNA was extracted from yeast cells by the hot phenol method (Collart & Oliviero 1993). Genomic DNA was extracted from yeast cells using "Dr GenTLE" kit (Takara), and used as a template for PCR amplification of the HAC1 gene with the primer set 5'-GAACAACAACTTATTTTTACAATGA-3' and 5'-AATAGACAGATAGATATGACACAA-3'.
Microarray analysis
Microarray analysis was performed as described in Ohdate et al. (2003) using Yeast Chip, version 3.0 (Hitachi Software Engineering). Briefly, mRNA was enriched from total RNA by oligo(dT) chromatography (mRNA purification kit, Amersham), and used as a template for reverse transcription from (dT)18 primer in a reaction mixture containing either Cy3- or Cy5-conjugated dUTP. The Cy3-labeled cDNA pool was mixed with the Cy5-labeled cDNA pool made from another RNA sample, and competitive hybridization on a microarray was performed. Fluorescent array images were obtained for Cy3 and Cy5 emissions by using a ScanArray Lite (PerkinElmer Life Sciences) scanner. Image intensity data were analyzed by using QuantArray 3.0 (PerkinElmer Life Sciences) software, and the expression ratio (Cy3 (or Cy5) signal intensity/Cy5 (or Cy3) signal intensity) of each gene was calculated. Experiments were done in duplicate, and highly irreproducible data were discarded. Spots that had mean intensity values of less than 1000 arbitrary units were also discarded.
Details in the microarray analysis are shown in the GEO database (http://www.ncbi.nlm.nih.gov/projects/geo/index.cgi) under the accession number GPL2940 [NCBI GEO] .
Northern blotting
Northern blot analysis of total RNA was performed as previously described (Kimata et al. 2003, 2004). Radiolabeled probes were prepared by random prime labeling (Takara) of the following gene fragments, all of which were obtained by PCR amplification of genomic DNA of BY4742; ACT1 (nt position –160–1424), ATO3 (nt position 3–618), ELO1 (nt position 126–678), HAC1 (nt position –11–654), SIL1 (nt position 73–610), TIP1 (nt position 71–622), TPO1 (136–702), TSA1 (nt position –24–621) and Ty2 transposon (PCR amplified using a primer set 5'-AACAATATCAATGTTAGCGACAGAT-3', 5'-CGTTGTCATCGCTTAAGTATTGTG-3').
Databases
We used the following databases in this study: the Comprehensive Yeast Genome Database (http://mips.gsf.de/desc/yeast/), the Saccharomyces Genome Database (http://www.yeastgenome.org/) and the YPD (http://www.proteome.com/).
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: kimata{at}zero.ad.jp, kimata{at}bs.naist.jp, kkouno{at}bs.naist.jp
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References |
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Received: 22 June 2005
Accepted: 3 October 2005
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