Virus Induction of Heat Shock Protein 70 Reflects a General Response to Protein Accumulation in the Plant Cytosol

Aparicio, Frederic; Thomas, Colwyn M.; Lederer, Carsten W.; Niu, Yan; Wang, Daowen; Maule, Andrew J.

doi:10.1104/pp.104.058958

Cited by 109 publications

(91 citation statements)

References 36 publications

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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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…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%

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

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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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“…The Arabidopsis genome encodes five soluble cytosolic HSP70s, HSP70 (referred to as HSP70A in this article) and HSP70B, and three constitutively expressed HSPs, HSC70-1, HSC70-2, and HSC70-3. All of these genes are induced by heat shock treatment, whereas all but HSP70B are induced in the CPR (Aparicio et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…These are not ubiquitous processes within the cell but are compartmentalized. Hence, the unfolded protein response (UPR), which is induced by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), recruits specific genes and pathways to regulate protein repair in that compartment (Ron and Walter, 2007), and a parallel process, the cytosolic protein response (CPR), operates in the cytosol (Aparicio et al, 2005). Although these processes are essential for maintaining normal cellular function under adverse conditions, how they are integrated into the wider response has been little investigated in higher eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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In common with a range of environmental and biological stresses, heat shock results in the accumulation of misfolded proteins and a collection of downstream consequences for cellular homeostasis and growth. Within this complex array of responses, the sensing of and responses to misfolded proteins in specific subcellular compartments involves specific chaperones, transcriptional regulators, and expression profiles. Using biological (ectopic protein expression and virus infection) and chemical triggers for misfolded protein accumulation, we have profiled the transcriptional features of the response to misfolded protein accumulation in the cytosol (i.e., the cytoplasmic protein response [CPR]) and identified the effects as a subcomponent of the wider effects induced by heat shock. The CPR in Arabidopsis thaliana is associated with the heat shock promoter element and the involvement of specific heat shock factors (HSFs), notably HSFA2, which appears to be regulated by alternative splicing and non-sense-mediated decay. Characterization of Arabidopsis HSFA2 knockout and overexpression lines showed that HSFA2 is one of the regulatory components of the CPR.

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Virus Induction of Heat Shock Protein 70 Reflects a General Response to Protein Accumulation in the Plant Cytosol

Cited by 109 publications

References 36 publications

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

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

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

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

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