Peroxiredoxin Chaperone Activity Is Critical for Protein Homeostasis in Zinc-deficient Yeast*

MacDiarmid, Colin W.; Taggart, Janet; Kerdsomboon, Kittikhun; Kubisiak, Michael; Panascharoen, Supawee; Schelble, Katherine; Eide, David J.

doi:10.1074/jbc.m113.512384

Cited by 58 publications

(79 citation statements)

References 84 publications

(74 reference statements)

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“…Because intracellular conditions are highly reducing and Prx concentrations typically are much higher than the k d of decamerization, much of the cellular Prx will be in its chaperoneactivatable form, making posttranslational modifications likely unnecessary to achieve chaperone function in vivo. What appears to be necessary for chaperone activation of Prx, however, is a structural remodeling of the decameric structure, which can be induced by elevated temperatures (an inherent part of most in vitro chaperone assays) and possibly by low pH or other proteinunfolding stress conditions, such as oxidative stress (33). In conclusion, our data suggest that Prxs are capable of integrating different unfolding stimuli and translating them into structural rearrangements that trigger chaperone activation.…”

Section: Discussionmentioning

confidence: 79%

Mitochondrial peroxiredoxin functions as crucial chaperone reservoir inLeishmania infantum

Teixeira

Castro

Cruz

et al. 2015

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

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Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum, mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx's ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx's chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.chaperone | Leishmania | peroxiredoxin

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Section: Discussionmentioning

confidence: 79%

Mitochondrial peroxiredoxin functions as crucial chaperone reservoir inLeishmania infantum

Teixeira

Castro

Cruz

et al. 2015

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

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“…Our initial studies indicated a role of the Tsa1 peroxidase activity in protecting zinc-deficient cells against an elevated level of reactive oxygen species in zinc-deficient cells. More recently, we found that the Tsa1 protein chaperone activity was more important than the peroxidase function for growth in zinc-deficient conditions (21). Zinc-deficient cells lacking Tsa1 chaperone activity accumulated elevated levels of stress-responsive protein chaperones, suggesting elevated unfolded protein accumulation and a corresponding heat shock response.…”

Section: Fet4mentioning

confidence: 99%

“…To test this hypothesis, we first analyzed the activity of the heat shockregulated transcription factor Hsf1, which responds to unfolded protein accumulation. Changes in Hsf1 activity in response to zinc status and UBI4 genotype were measured using a synthetic HSE-lacZ reporter gene (21). Reporter activity was strongly induced by a 1-h heat shock at 37°in both wildtype and ubi4⌬ zinc-replete cells (Fig.…”

Section: Reduction Of Proteasome Activity Suppresses the Ubi4⌬mentioning

confidence: 99%

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

MacDiarmid

Taggart

Jeong

et al. 2016

Journal of Biological Chemistry

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Stability of many proteins requires zinc. Zinc deficiency disrupts their folding, and the ubiquitin-proteasome system may help manage this stress. In Saccharomyces cerevisiae, UBI4 encodes five tandem ubiquitin monomers and is essential for growth in zinc-deficient conditions. Although UBI4 is only one of four ubiquitin-encoding genes in the genome, a dramatic decrease in ubiquitin was observed in zinc-deficient ubi4⌬ cells. The three other ubiquitin genes were strongly repressed under these conditions, contributing to the decline in ubiquitin. In a screen for ubi4⌬ suppressors, a hypomorphic allele of the RPT2 proteasome regulatory subunit gene (rpt2 E301K ) suppressed the ubi4⌬ growth defect. The rpt2 E301K mutation also increased ubiquitin accumulation in zinc-deficient cells, and by using a ubiquitin-independent proteasome substrate we found that proteasome activity was reduced. These results suggested that increased ubiquitin supply in suppressed ubi4⌬ cells was a consequence of more efficient ubiquitin release and recycling during proteasome degradation. Degradation of a ubiquitin-dependent substrate was restored by the rpt2 E301K mutation, indicating that ubiquitination is rate-limiting in this process. The UBI4 gene was induced ϳ5-fold in low zinc and is regulated by the zinc-responsive Zap1 transcription factor. Surprisingly, Zap1 controls UBI4 by inducing transcription from an intragenic promoter, and the resulting truncated mRNA encodes only two of the five ubiquitin repeats. Expression of a short transcript alone complemented the ubi4⌬ mutation, indicating that it is efficiently translated. Loss of Zap1-dependent UBI4 expression caused a growth defect in zinc-deficient conditions. Thus, the intragenic UBI4 promoter is critical to preventing ubiquitin deficiency in zinc-deficient cells.Zinc is an essential element with diverse roles in biology. Unlike transition metals, such as iron and copper, zinc ions (Zn 2ϩ ) are not redox-active under physiological conditions and do not play a direct role in redox reactions. Zn 2ϩ strongly interacts with ligands, such as cysteine, histidine, and acidic amino acids in proteins (1). When bound by three or fewer ligands, Zn 2ϩ can act as a Lewis acid to facilitate catalysis by diverse classes of enzymes, including oxidoreductases, transferases, and hydrolases (2). In contrast, binding of Zn 2ϩ by four ligands produces a relatively inert, structurally rigid tetrahedral complex, which provides stability to many classes of protein domains (1-3). Because of its catalytic and structural roles, Zn 2ϩ has been estimated to be required for the folding and function of ϳ10% of proteins encoded by eukaryotic genomes and ϳ5% of proteins in prokaryotes (4, 5). One abundant example is the enzyme alcohol dehydrogenase, which contains two Zn 2ϩ atoms per subunit, one serving in catalysis and the other playing a structural role (1, 6, 7). Consistent with the importance of zinc to Adh 2 folding, mutants of Adh lacking structural zinc site ligands are unstable and quickly degraded in ...

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“…In zinc-deficient conditions, however, atg41Δ 410 cells showed ~15-fold higher -galactosidase activity than in wild-type cells, indicating strong 411 activation of the SSA3 promoter. To confirm this phenotype, we used a second reporter with a 412 single heat shock element (HSE) inserted upstream of a basal promoter to drive expression of 413 lacZ (MACDIARMID et al 2013) and assayed -galactosidase activity in zinc-replete and 414 deficient wild-type and atg41Δ cells. This reporter also showed increased activity specifically in 415 zinc-limited atg41Δ mutants (Fig.…”

Section: Process 401 402mentioning

confidence: 99%

“…The 35 CTT1 catalase gene is also induced by Zap1 and this response is likely to eliminate the 36 oxidative stress that arises during zinc deficiency. The protein chaperones Hsp26 and Tsa1 37 are induced to deal with unfolded protein stress that might occur due to lack of this important 38 structural cofactor, and UBI4, encoding ubiquitin, is activated by Zap1 to maintain levels of this 39 critical stress protein (MACDIARMID et al 2013;MACDIARMID et al 2016). Thus, Zap1 plays 40 important roles in maintaining zinc homeostasis and adapting the cell to zinc-deficient growth.…”

Section: Introduction 21mentioning

confidence: 99%

An Autophagy-Independent Role for ATG41 in Sulfur Metabolism During Zinc Deficiency

et al. 2018

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1The Zap1 transcription factor of Saccharomyces cerevisiae is a key regulator in the genomic 2 responses to zinc deficiency. Among the genes regulated by Zap1 during zinc deficiency is the 3 autophagy-related gene ATG41. Here, we report that Atg41 is required for growth in zinc-4 deficient conditions but not when zinc is abundant or when other metals are limiting. 5Consistent with a role for Atg41 in macroautophagy, we show that nutritional zinc deficiency 6 induces autophagy and that mutation of ATG41 diminishes that response. Several experiments 7 indicated that the importance of ATG41 function to growth during zinc deficiency is not 8 because of its role in macroautophagy but rather is due to one or more autophagy-independent 9 functions. For example, rapamycin treatment fully induced autophagy in zinc-deficient atg41Δ 10 mutants but failed to improve growth. In addition, atg41Δ mutants showed a far more severe 11 growth defect than any of several other autophagy mutants tested, and atg41Δ mutants 12 showed increased Hsf1 activity, an indicator of protein homeostasis stress, while other 13 autophagy mutants did not. An autophagy-independent function for ATG41 in sulfur 14 metabolism during zinc deficiency was suggested by analyzing the transcriptome of atg41Δ 15 mutants during the transition from zinc-replete to deficient conditions. Analysis of sulfur 16 metabolites confirmed that Atg41 is needed for the normal accumulation of methionine, 17 homocysteine, and cysteine in zinc-deficient cells. Therefore, we conclude that Atg41 plays 18 roles in both macroautophagy and sulfur metabolism during zinc deficiency. 19 20 4

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Peroxiredoxin Chaperone Activity Is Critical for Protein Homeostasis in Zinc-deficient Yeast*

Cited by 58 publications

References 84 publications

Mitochondrial peroxiredoxin functions as crucial chaperone reservoir inLeishmania infantum

Mitochondrial peroxiredoxin functions as crucial chaperone reservoir inLeishmania infantum

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

An Autophagy-Independent Role for ATG41 in Sulfur Metabolism During Zinc Deficiency

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