The Cytosolic Protein Response as a Subcomponent of the Wider Heat Shock Response in<i>Arabidopsis</i>

Sugio, Akiko; Dreos, René; Aparicio, Frederic; Maule, Andrew J.

doi:10.1105/tpc.108.062596

Cited by 197 publications

(230 citation statements)

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“…The CPR is the cellular response corresponding to the accumulation of unfolded proteins in the cytoplasm, but not in the ER, and the UPR genes induced by Tm were excluded from the CPR genes (18). This observation can be interpreted as follows.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that a cellular response different from the UPR occurs in the cytosol if protein folding in the cytosol is disturbed. This response is referred to as the cytosolic protein response (CPR) (17), and genes induced in the CPR in Arabidopsis were identified by microarray-excluding genes induced in the UPR (18). However, 30 of 190 genes up-regulated by Tm in ire1a/b were overlapped with the CPR genes, similar to the heat stress-responsive genes (Fig.…”

Section: Up-regulation Of Cytosolic Protein Response Genes In Ire1a/bmentioning

confidence: 99%

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Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Mishiba

Nagashima

Suzuki

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

167

172

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The unfolded protein response (UPR) is a cellular response highly conserved in eukaryotes to obviate accumulation of misfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring enzyme 1 (IRE1) catalyzes the cytoplasmic splicing of mRNA encoding bZIP transcription factors to activate the UPR signaling pathway. Arabidopsis IRE1 was recently shown to be involved in the cytoplasmic splicing of bZIP60 mRNA. In the present study, we demonstrated that an Arabidopsis mutant with defects in two IRE1 paralogs showed enhanced cell death upon ER stress compared with a mutant with defects in bZIP60 and wild type, suggesting an alternative function of IRE1 in the UPR. Analysis of our previous microarray data and subsequent quantitative PCR indicated degradation of mRNAs encoding secretory pathway proteins by tunicamycin, DTT, and heat in an IRE1-dependent manner. The degradation of mRNAs localized to the ER during the UPR was considered analogous to a molecular mechanism referred to as the regulated IRE1-dependent decay of mRNAs reported in metazoans. Another microarray analysis conducted in the condition repressing transcription with actinomycin D and a subsequent Gene Set Enrichment Analysis revealed the regulated IRE1-dependent decay of mRNAs-mediated degradation of a significant portion of mRNAs encoding the secretory pathway proteins. In the mutant with defects in IRE1, genes involved in the cytosolic protein response such as heat shock factor A2 were upregulated by tunicamycin, indicating the connection between the UPR and the cytosolic protein response.heat stress | protein folding | bioinformatics T he unfolded protein response (UPR) or the endoplasmic reticulum (ER) stress response is a cellular response that is highly conserved in eukaryotes to obviate accumulation of misfolded proteins and to alleviate protein overload in the ER (1-3). Inositol-requiring enzyme 1 (IRE1), which is the primary transducer of the UPR in various organisms, catalyzes the unconventional or cytoplasmic splicing of mRNAs encoding bZIP transcription factors to up-regulate the UPR-related genes, such as genes for the ER-resident molecular chaperones, through its ribonuclease domain. The cytoplasmic splicing by IRE1 activates the bZIP transcription factors HAC1, XBP1, and bZIP60 in yeast, animals, and plants, respectively, by producing active proteins. Although the fundamental mechanism of the cytoplasmic splicing by IRE1 appears to be highly conserved, the mechanism of transcription factor activation is diverse among organisms (4).In addition to the cytoplasmic splicing of mRNAs for transcription factors, other functions of metazoan IRE1 have been reported. One such function is the degradation of mRNAencoding proteins in the secretory pathway referred to as regulated IRE1-dependent decay (RIDD) (5-7). RIDD is considered to contribute to reducing the amount of proteins entering the ER in the UPR. The metazoan UPR has an alternative mechanism to reduce the amount of protein entering the ER, and this mechanism is regulated by PKR-li...

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Section: Discussionmentioning

confidence: 99%

Section: Up-regulation Of Cytosolic Protein Response Genes In Ire1a/bmentioning

confidence: 99%

Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Mishiba

Nagashima

Suzuki

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

167

172

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“…Several previous studies have concluded that misfolded proteins induce a subset of the heat-shock response in bacterial (17), fungal (35), plant (13,14), and vertebrate cells (40) by either monitoring transcript or protein changes in response to widespread misfolding (13,35) or monitoring only a handful of heatshock proteins (13,14,17,40). Recent studies have led to the proposal that the UPR-Cyto is a specific HSF1-mediated module of the eukaryotic heat-shock response (13,15).…”

Section: Discussionmentioning

confidence: 99%

“…In the eukaryotic endoplasmic reticulum (ER), misfolded proteins provoke the unfolded protein response (UPR) (11), whereas in the cytosol, a broader heat-shock response combats protein misfolding, oxidative stress, altered membrane integrity, and reduced growth rate (12). Recent work suggests that the heat-shock response may mask a milder and more targeted response to counteract cytosolic protein misfolding (13)(14)(15), dubbed the UPR-Cyto (15), but the molecular components of this response remain unclear.…”

mentioning

confidence: 99%

Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast

Geiler-Samerotte

Dion

Budnik

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

278

298

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Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein.Comparable experiments on variants of the yeast gene orotidine-5′-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution.proteomics | stability | heat shock | evolutionary rate M ost new genetic mutations arising in protein-coding sequences decrease the likelihood that the encoding protein will fold properly (1, 2). Misfolding reduces the concentration of functional proteins, squanders cellular time and energy on production of useless proteins (3), and generates misfolded proteins that may harm cells (4). Given the high probability and diverse effects of failed protein folding, isolating and quantifying the influences of misfolding on fitness are essential for the development of mechanistic answers to fundamental questions in evolutionary biology: the distribution of fitness effects of new mutations, the interpretation of varying rates of molecular evolution, and the significance of compensatory mutations. Understanding how misfolding affects cell fitness may also illuminate the molecular basis of human diseases, particularly neurological disorders linked to misfolded protein toxicity (4, 5).Patterns of coding sequence evolution across taxa depend strongly on gene expression, with apparently limited contribution from protein function (6, 7). This has led to the misfolding hypothesis: that within-genome variation in purifying selection on coding sequences is predominantly shaped by the fitness cost of misfolded proteins and therefore, correlates with gene expression and protein abundance (8,9). It predicts that...

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“…The functional HSE element usually contains a minimum of three 5′nGAAn3′ repeated motifs with a maximum insertion of 5 bp between each motif. Sugio et al (2009) …”

Section: Introductionmentioning

confidence: 99%

OsHsfA2c and OsHsfB4b are involved in the transcriptional regulation of cytoplasmic OsClpB (Hsp100) gene in rice (Oryza sativa L.)

Singh

Mittal

Lavania

et al. 2012

Cell Stress and Chaperones

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ClpB-cytoplasmic (ClpB-cyt)/Hsp100 is an important chaperone protein in rice. Cellular expression of OsClpB-cyt transcript is governed by heat stress, metal stress, and developmental cues. Transgenic rice plants produced with 2 kb OsClpB-cyt promoter driving Gus reporter gene showed heat-and metal-regulated Gus expression in vegetative tissues and constitutive Gus expression in calli, flowering tissues, and embryonal half of seeds. Rice seedlings regenerated with OsClpB-cyt promoter fragment with deletion of its canonical heat shock element sequence (HSE −273 to −280 ) showed not only heat shock inducibility of Gus transcript/protein but also constitutive expression of Gus in vegetative tissues. It thus emerges that the only classical HSE present in OsClpB-cyt promoter is involved in repressing expression of OsClpB-cyt transcript under unstressed control conditions. Yeast onehybrid assays suggested that OsHsfA2c specifically interacts with OsClpB-cyt promoter. OsHsfA2c also showed binding with OsClpB-cyt and OsHsfB4b showed binding with OsClpB-cyt; notably, interaction of OsHsfB4b was seen for all three OsClpB/Hsp100 protein isoforms (i.e., ClpBcytoplasmic, ClpB-mitochondrial, and ClpB-chloroplastic).Furthermore, OsHsfB4b showed interaction with OsHsfA2c. This study suggests that OsHsfA2c may play a role as transcriptional activator and that OsHsfB4b is an important part of this heat shock responsive circuitry.

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The Cytosolic Protein Response as a Subcomponent of the Wider Heat Shock Response inArabidopsis

Cited by 197 publications

References 44 publications

Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast

OsHsfA2c and OsHsfB4b are involved in the transcriptional regulation of cytoplasmic OsClpB (Hsp100) gene in rice (Oryza sativa L.)

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