Severe ethanol stress induces the preferential synthesis of mitochondrial disaggregase Hsp78 and formation of DUMPs in Saccharomyces cerevisiae

Yu, I.; Nishino, Seiya; Fukuda, Shizu; Nguyet, Vo Thi Anh; Izawa, Shingo

doi:10.1016/j.bbagen.2022.130147

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…Other amino acid biosynthesis proteins, namely Aat2, Arg4, Arg7, Asn1, Asn2, His1, His4, His5, Hom2, Hom3, Idp1, Leu4, Lys12, Lys20, Leu9, Trp2, Trp3, Trp4, and Trp5, were upregulated in the long-lived yeast strains (Figure 2D) [57]. In our dataset, we found that Hsp78, which prevents misfolded protein aggregation, and Sgt2, which interacts with prion aggregates and is an amyloid sensor, also showed differential protein abundances in the long-lived yeast strains [58][59][60][61][62][63][64][65]. Altogether, these data suggest that GCN4 impacts the transcription of genes involved in protein synthesis and stabilization, which is in agreement with the results of other studies [34,[66][67][68].…”

Section: Gcn4 Impacts Proteins Related To Amino Acid Biosynthesis In ...mentioning

confidence: 68%

Multiomics of GCN4-Dependent Replicative Lifespan Extension Models Reveals Gcn4 as a Regulator of Protein Turnover in Yeast

Mariner,

Felker,

Cantergiani

et al. 2023

IJMS

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We have shown that multiple tRNA synthetase inhibitors can increase lifespan in both the nematode C. elegans and the budding yeast S. cerevisiae by acting through the conserved transcription factor Gcn4 (yeast)/ATF-4 (worms). To further understand the biology downstream from this conserved transcription factor in the yeast model system, we looked at two different yeast models known to have upregulated Gcn4 and GCN4-dependent increased replicative lifespan. These two models were rpl31aΔ yeast and yeast treated with the tRNA synthetase inhibitor borrelidin. We used both proteomic and RNAseq analysis of a block experimental design that included both of these models to identify GCN4-dependent changes in these two long-lived strains of yeast. Proteomic analysis of these yeast indicate that the long-lived yeast have increased abundances of proteins involved in amino acid biosynthesis. The RNAseq of these same yeast uncovered further regulation of protein degradation, identifying the differential expression of genes associated with autophagy and the ubiquitin–proteasome system (UPS). The data presented here further underscore the important role that GCN4 plays in the maintenance of protein homeostasis, which itself is an important hallmark of aging. In particular, the changes in autophagy and UPS-related gene expression that we have observed could also have wide-ranging implications for the understanding and treatment of diseases of aging that are associated with protein aggregation.

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Section: Gcn4 Impacts Proteins Related To Amino Acid Biosynthesis In ...mentioning

confidence: 68%

Multiomics of GCN4-Dependent Replicative Lifespan Extension Models Reveals Gcn4 as a Regulator of Protein Turnover in Yeast

Mariner,

Felker,

Cantergiani

et al. 2023

IJMS

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“…Recent work has demonstrated that during aging and upon exposure to environmental stress, protein aggregates form in the cytosol and the mitochondrial matrix 13–15 . Here, ClpB‐type unfoldases like the cytosolic Hsp104 and its mitochondrial homolog Hsp78 decorate these aggregates and dissolve them through extraction of individual polypeptides 16–19 . Hsp78 contains, like the other ClpB homologs, a substrate binding domain as well as an associated AAA‐type of ATPase, which is used to unfold a bound protein by threading through a central pore 20 .…”

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 , 15 Here, ClpB‐type unfoldases like the cytosolic Hsp104 and its mitochondrial homolog Hsp78 decorate these aggregates and dissolve them through extraction of individual polypeptides. 16 , 17 , 18 , 19 Hsp78 contains, like the other ClpB homologs, a substrate binding domain as well as an associated AAA‐type of ATPase, which is used to unfold a bound protein by threading through a central pore. 20 Due to the interdependency between cytosolic and mitochondrial metabolism, the metabolic state of the cell likely determines the efficiency with which the mitochondrial PQC system operates.…”

Section: Introductionmentioning

confidence: 99%

Newly imported proteins in mitochondria are particularly sensitive to aggregation

et al. 2023

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Aim A functional proteome is essential for life and maintained by protein quality control (PQC) systems in the cytosol and organelles. Protein aggregation is an indicator of a decline of PQC linked to aging and disease. Mitochondrial PQC is critical to maintain mitochondrial function and thus cellular fitness. How mitochondria handle aggregated proteins is not well understood. Here we tested how the metabolic status impacts on formation and clearance of aggregates within yeast mitochondria and assessed which proteins are particularly sensitive to denaturation. Methods Confocal microscopy, electron microscopy, immunoblotting and genetics were applied to assess mitochondrial aggregate handling in response to heat shock and ethanol using the mitochondrial disaggregase Hsp78 as a marker for protein aggregates. Results We show that aggregates formed upon heat or ethanol stress with different dynamics depending on the metabolic state. While fermenting cells displayed numerous small aggregates that coalesced into one large foci that was resistant to clearance, respiring cells showed less aggregates and cleared these aggregates more efficiently. Acute inhibition of mitochondrial translation had no effect, while preventing protein import into mitochondria by inhibition of cytosolic translation prevented aggregate formation. Conclusion Collectively, our data show that the metabolic state of the cells impacts the dynamics of aggregate formation and clearance, and that mainly newly imported and not yet assembled proteins are prone to form aggregates. Because mitochondrial functionality is crucial for cellular metabolism, these results highlight the importance of efficient protein biogenesis to maintain the mitochondrial proteome operational during metabolic adaptations and cellular stress.

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Acquired resistance to severe ethanol stress-induced inhibition of proteasomal proteolysis in Saccharomyces cerevisiae

Nguyet

Furutani

Ando

et al. 2022

Biochimica et Biophysica Acta (BBA) - General Subjects

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Severe ethanol stress induces the preferential synthesis of mitochondrial disaggregase Hsp78 and formation of DUMPs in Saccharomyces cerevisiae

Cited by 6 publications

References 55 publications

Multiomics of GCN4-Dependent Replicative Lifespan Extension Models Reveals Gcn4 as a Regulator of Protein Turnover in Yeast

Multiomics of GCN4-Dependent Replicative Lifespan Extension Models Reveals Gcn4 as a Regulator of Protein Turnover in Yeast

Newly imported proteins in mitochondria are particularly sensitive to aggregation

Acquired resistance to severe ethanol stress-induced inhibition of proteasomal proteolysis in Saccharomyces cerevisiae

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