Distinct classes of misfolded proteins differentially affect the growth of yeast compromised for proteasome function

Burns, Grace D; Hilal, Olivia E; Sun, Zhihao; Reutter, Karl-Richard; Preston, Gregory M.; Augustine, Andrew A.; Brodsky, Jeffrey L.; Guerriero, Christopher J.

doi:10.1002/1873-3468.14172

Cited by 4 publications

(4 citation statements)

References 81 publications

(116 reference statements)

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“…As with dfm1Δ cells, this effect was specific to membrane protein expression, as expression of CPY* in rpn4Δ cells did not result in a growth defect ( S4B Fig ). This is in line with previous research demonstrating Rpn4 is activated in response to misfolded membrane protein accumulation and that misfolded membrane protein expression can result in proteasome impairment, even in WT cells [ 54 , 55 ]. Finally, we tested a transcription factor that can regulate Rpn4 and has many overlapping transcriptional targets with Rpn4, Pdr1 [ 56 ], and did not observe any growth defect in pdr1Δ +Hmg2 cells ( S4C Fig ).…”

Section: Resultssupporting

confidence: 92%

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

et al. 2023

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Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.

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Section: Resultssupporting

confidence: 92%

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

et al. 2023

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“…Furthermore, a recent study has shown that expression of a cytoplasmic model misfolded protein NBD2* in the rpn4 mutant did not lead to slower cell growth, while the expression of several membrane misfolded mutant proteins resulted in slower growth of the rpn4 mutant. 65 Based on that finding, it is possible that protein quality control mutants other than rpn4 may have a synthetic phenotype with human tau.…”

Section: Discussionmentioning

confidence: 99%

“…membrane misfolded mutant proteins resulted in slower growth of the rpn4 mutant. 65 Based on that finding, it is possible that protein quality control mutants other than rpn4 may have a synthetic phenotype with human tau.…”

Section: Discussionmentioning

confidence: 99%

Effects of heterologous human tau protein expression in yeast models of proteotoxic stress response

et al. 2023

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BackgroundThe primary histological characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which are large aggregates of tau protein. Aging is the primary risk factor for the development of Alzheimer's disease, however, the underlying causes of tau protein aggregation and toxicity are unclear.AimsHere we investigated tau aggregation and toxicity under the conditions of compromised protein homeostasis.MethodsWe used heterologous expression of human tau protein in the unicellular eukaryote yeast Saccharomyces cerevisiae with evolutionarily conserved protein quality control pathways and examined tau‐dependent toxicity and aggregation using growth assays, fluorescence microscopy, and a split luciferase‐based reporter NanoBiT.ResultsTau protein expressed in yeast under mild proteotoxic stress, or in mutants with impaired pathways for proteotoxic stress response, did not lead to synthetic toxicity or the formation of obvious aggregates. Chronologically old cells also did not develop observable tau aggregates. Our examination of tau oligomerization in living cells using NanoBiT reporter suggests that tau does not form significant levels of oligomers under basal conditions or under mild proteotoxic stress.ConclusionTogether our data suggest that human tau protein does not represent a major burden to the protein quality control system in yeast cells.

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“…Maintenance of the proteome is important in the stress response system [4]. This dynamic equilibrium is mediated by the coupling of ubiquitin with intracellular proteins for their selective degradation in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

The Protein Response of Salt-Tolerant Zygosaccharomyces rouxii to High-Temperature Stress during the Lag Phase

Hu,

Xiao,

Yao

et al. 2024

JoF

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Zygosaccharomyces rouxii used in soy sauce brewing is an osmotolerant and halotolerant yeast, but it is not tolerant to high temperatures and the underlying mechanisms remain poorly understood. Using a synthetic medium containing only Pro as a nitrogen source, the response of Z. rouxii in protein level to high-temperature stress (40 °C, HTS) during the lag phase was investigated. Within the first two h, the total intracellular protein concentration was significantly decreased from 220.99 ± 6.58 μg/mg DCW to 152.63 ± 10.49 μg/mg DCW. The analysis of the amino acid composition of the total protein through vacuum proteolysis technology and HPLC showed that new amino acids (Thr, Tyr, Ser, and His) were added to newborn protein over time during the lag phase under HTS. The nutritional conditions used in this study determined that the main source of amino acid supply for protein synthesis was through amino acid biosynthesis and ubiquitination-mediated protein degradation. Differential expression analysis of the amino acid biosynthesis-related genes in the transcriptome showed that most genes were upregulated under HTS, excluding ARO8, which was consistently repressed during the lag phase. RT-qPCR results showed that high-temperature stress significantly increased the upregulation of proteolysis genes, especially PSH1 (E3 ubiquitin ligase) by 13.23 ± 1.44 fold (p < 0.0001) within 4 h. Overall, these results indicated that Z. rouxii adapt to prolonged high temperatures stress by altering its basal protein composition. This protein renewal was related to the regulation of proteolysis and the biosynthesis of amino acids.

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Distinct classes of misfolded proteins differentially affect the growth of yeast compromised for proteasome function

Cited by 4 publications

References 81 publications

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

Effects of heterologous human tau protein expression in yeast models of proteotoxic stress response

The Protein Response of Salt-Tolerant Zygosaccharomyces rouxii to High-Temperature Stress during the Lag Phase

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