The Heat Shock Response in Yeast Maintains Protein Homeostasis by Chaperoning and Replenishing Proteins

Mühlhofer, Moritz; Berchtold, Evi; Stratil, Chris G.; Csaba, Gergely; Kunold, Elena; Bach, Nina C.; Sieber, Stephan A.; Haslbeck, Martin; Zimmer, Ralf; Büchner, Johannes

doi:10.1016/j.celrep.2019.11.109

Cited by 90 publications

(93 citation statements)

References 66 publications

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“…Interestingly, from our ten most upregulated proteins, only heat shock proteins were also upregulated on mRNA level; other proteins were upregulated only at the protein level ( Fig 4G) suggesting that their upregulation is translation rather than transcription driven. Similar findings have been made with yeast [45].…”

Section: Reversible Stall In Protein Synthesis After Heat Shocksupporting

confidence: 89%

Aggregation and Disaggregation Features of the Human Proteome

Määttä

Rettel

Helm

et al. 2020

Preprint

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Protein aggregates have negative implications in disease. While reductionist experiments have increased our understanding of aggregation processes, the systemic view in biological context is still limited. To extend this understanding, we used mass spectrometry-based proteomics to characterize aggregation and disaggregation in human cells after non-lethal heat shock. Aggregation-prone proteins were enriched in nuclear proteins, high proportion of intrinsically disordered regions, high molecular mass, high isoelectric point and hydrophilic amino acids. During recovery, most aggregating proteins disaggregated with a rate proportional to the aggregation propensity: larger loss in solubility was counteracted by faster disaggregation. High amount of intrinsically disordered regions also resulted in faster disaggregation. However, other characteristics enriched in aggregating proteins did not correlate with the disaggregation rates. In addition, we analyzed changes in protein thermal stability after heat shock. Soluble remnants of aggregated proteins were more thermally stable compared to control condition. Our results provide a rich resource of heat stress-related protein solubility data, propose novel roles for intrinsically disordered regions in protein quality control and reveal a protection mechanism to repress protein aggregation in heat stress.

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Section: Reversible Stall In Protein Synthesis After Heat Shocksupporting

confidence: 89%

Aggregation and Disaggregation Features of the Human Proteome

Määttä

Rettel

Helm

et al. 2020

Preprint

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“…Further, this kind of time lag between stress and response is a general phenomenon observed in several model organisms. For example, in yeast, delayed proteomic response is observed under severe heat stress leading to delayed HSR (46). Similar delayed response was also observed in C. elegans under 34 deg Celsius high heat stress for 1 hour (15).…”

Section: Discussionsupporting

confidence: 64%

“…One is that the total protein copy number is conserved due to the associated energy cost in increasing gene expression (45). Also, proteins lost as irreversible aggregates due to very high stresses are replenished by translation which ensures protein homeostasis (46). We have incorporated this phenomenon in our models and simulations in the form of Eq.…”

Section: Discussionmentioning

confidence: 99%

A mathematical model of heat shock response to study the competition between protein folding and aggregation

Pal

Sharma

2020

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Proteins, under conditions of cellular stress, typically tend to unfold and form lethal aggregates leading to neurological diseases like Parkinson's and Alzheimer's. A clear understanding of the conditions that favor dis-aggregation and restore the cell to its healthy state after they have been stressed is therefore important in dealing with these diseases. The heat shock response (HSR) mechanism is a signaling network that deals with these undue protein aggregates and aids in the maintenance of homeostasis within a cell. This framework, on its own, is a mathematically well studied mechanism. However, not much is known about how the various intermediate mis-folded protein states of the aggregation process interact with some of the key components of the HSR pathway such as the Heat Shock Protein (HSP), the Heat Shock transcription Factor (HSF) and the HSP-HSF complex. In this article, using already validated parameters from the literature, we propose and analyze two mathematical models for HSR that also include explicit reactions for the formation of protein aggregates. Deterministic analysis and stochastic simulations of these models show that the folded proteins and the misfolded aggregates exhibit bistability in a certain region of the parameter space. Further, the models also highlight the role of HSF and the HSF-HSP complex in reducing the time lag of response to stress and in re-folding all the mis-folded proteins back to their native state. These models therefore call attention to the significance of studying related pathways such as the HSR and the protein aggregation and re-folding process in conjunction with each other. Heat Shock Response | Signaling Pathway | Stochastic modeling | BistabilityCorrespondence: rati@iiserb.ac.in et al. | bioRχiv | April 13, 2020 | 1-10

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“…In the last two decades, heat-induced changes to the transcriptome and proteome have been well characterized [11][12][13][14][15][16][17] . In budding yeast, a shift from 30 to 37°C causes around a thousand genes to change transcription 11,17 , while exposure to 42°C results in expression changes for more than 50% of the yeast genome (~3100 genes), with higher magnitude and longer upkeep compared to 37°C 17 . Much less is known about the mechanisms that enable regulation of this response which is essential to safeguard cellular survival.…”

Section: Introductionmentioning

confidence: 99%

“…A comprehensive understanding of how signalling programmes integrate to regulate the HSR is missing. In addition, it is unclear which molecular branches of the HSR contribute to cellular protection, given that the bulk of heat-induced genes 17,28 is dispensable for tolerance to both acute and anticipated stress [41][42][43] .…”

Section: Introductionmentioning

confidence: 99%

Gene dosage screens in yeast reveal core signalling pathways controlling heat adaptation

Jann

Johansson²,

Smith

et al. 2020

Preprint

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Heat stress causes proteins to unfold and lose their function, jeopardizing essential cellular processes. To protect against heat and proteotoxic stress, cells mount a dedicated stress-protective programme, the so-called heat shock response (HSR). Our understanding of the mechanisms that regulate the HSR and their contributions to heat resistance and growth is incomplete. Here we employ CRISPRi/a to down- or upregulate protein kinases and transcription factors in S. cerevisiae. We measure gene functions by quantifying perturbation effects on HSR activity, thermotolerance, and cellular fitness at 23, 30 and 38°C. The integration of these phenotypes allowed us to identify core signalling pathways of heat adaptation and reveal novel functions for the high osmolarity glycerol, unfolded protein response and protein kinase A pathways in adjusting both thermotolerance and chaperone expression. We further provide evidence for unknown cross-talk of the HSR with the cell cycle-dependent kinase Cdc28, the primary regulator of cell cycle progression. Finally, we show that CRISPRi efficiency is temperature-dependent and that different phenotypes vary in their sensitivity to knock-down. In summary, our study quantifies regulatory gene functions in different aspects of heat adaptation and advances our understanding of how eukaryotic cells counteract proteotoxic and other heat-caused damage.

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The Heat Shock Response in Yeast Maintains Protein Homeostasis by Chaperoning and Replenishing Proteins

Abstract: Highlights d The HSR is modular and tuned to the severity of stress d 90% of the upregulation under stress is required to keep protein levels constant d Protein loss under stress is replenished by translation d Aggregation processes shape the sublethal heat stress response

Cited by 90 publications

References 66 publications

Aggregation and Disaggregation Features of the Human Proteome

Aggregation and Disaggregation Features of the Human Proteome

A mathematical model of heat shock response to study the competition between protein folding and aggregation

Gene dosage screens in yeast reveal core signalling pathways controlling heat adaptation

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