Heat Shock Response: Cellular and Molecular Responses to Stress, Misfolded Proteins, and Diseases Associated with Protein Aggregation

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of unfolded proteins initiates the synthesis of heat shock proteins through the heat shock transcription factor HSF1. While the molecular mechanisms are qualitatively well characterized, our quantitative understanding of the underlying dynamics is still very limited. Here, we study the dynamics of HSR in the photosynthetic model organism Chlamydomonas reinhardtii with a data-driven mathematical model of HSR. We based our dynamical model mostly on mass action kinetics, with a few nonlinear terms. The model was parametrized and validated by several independent datasets obtained from the literature. We demonstrate that HSR quantitatively and significantly differs if an increase in temperature of the same magnitude occurs abruptly, as often applied under laboratory conditions, or gradually, which would rather be expected under natural conditions. In contrast to rapid temperature increases, under gradual changes only negligible amounts of misfolded proteins accumulate, indicating that the HSR of C. reinhardtii efficiently avoids the accumulation of misfolded proteins under conditions most likely to prevail in nature. The mathematical model we developed is a flexible tool to simulate the HSR to different conditions and complements the current experimental approaches.

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Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells

10.1101/2020.01.06.896654 ◽

2020 ◽

Cited By ~ 1

Author(s):

R. San Gil ◽

D. Cox ◽

L. McAlary ◽

T. Berg ◽

A. K. Walker ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Heat Shock Response ◽

Flow Cytometric Analysis ◽

Protein Aggregates ◽

Shock Response ◽

Shock Proteins

AbstractProtein aggregation that results in the formation of inclusions is strongly correlated with neuronal death and is a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Cells are thought to dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via induction of the heat shock response (HSR). Heat shock proteins are well-characterised molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, or traffic protein for degradation. The reason why heat shock proteins are unable to maintain the solubility of particular proteins in neurodegenerative disease is unknown. We sought to determine whether neurodegenerative disease-associated protein aggregates can induce the HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter under conditions of HSR induction, for example heat shock. Using these cells, we show that the HSR is not induced by exogenous treatment with aggregated forms of Parkinson’s disease-associated α-synuclein or the ALS-associated G93A mutant of superoxide dismutase-1 (SOD1G93A). Furthermore, flow cytometric analysis revealed that intracellular expression of SOD1G93A or a pathogenic form of polyQ-expanded huntingtin (Htt72Q), similarly, results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels of the aggregation-prone proteins, but the pathogenic proteins (SOD1G93A and Htt72Q) elicit a significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results suggest that pathogenic proteins either evade detection or impair induction of the HSR in neuronal-like cells. Therefore, defective HSR induction may facilitate the initiation of protein aggregation leading to inclusion formation in neurodegenerative diseases.

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Impaired proteostasis in senescent vascular endothelial cells: a perspective on estrogen and oxidative stress in the aging vasculature

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00318.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. H421-H429 ◽

Cited By ~ 3

Author(s):

HyunTae V. Hwang ◽

Yun Lin ◽

Michelle N. Rebuffatti ◽

Darlene T. Tran ◽

Lily Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Heat Shock ◽

Protein Aggregation ◽

Cellular Senescence ◽

Heat Shock Response ◽

Human Endothelial Cells ◽

Early Passage ◽

Shock Response ◽

17Β Estradiol

The heat shock response is an important cytoprotective mechanism for protein homeostasis and is an essential protective response to cellular stress and injury. Studies on changes in the heat shock response with aging have been mixed with regard to whether it is inhibited, and this, at least in part, reflects different tissues and different models. Cellular senescence is a key feature in aging, but work on the heat shock response in cultured senescent (SEN) cells has largely been limited to fibroblasts. Given the prevalence of oxidative injury in the aging cardiovascular system, we investigated whether SEN primary human coronary artery endothelial cells have a diminished heat shock response and impaired proteostasis. In addition, we tested whether this downregulation of heat shock response can be mitigated by 17β-estradiol (E2), which has a critical cardioprotective role in women, as we have previously reported that E2 improves the heat shock response in endothelial cells (Hamilton KL, Mbai FN, Gupta S, Knowlton AA. Arterioscler Thromb Vasc Biol 24: 1628–1633, 2004). We found that SEN endothelial cells, despite their unexpectedly increased proteasome activity, had a diminished heat shock response and had more protein aggregation than early passage cells. SEN cells had increased oxidative stress, which promoted protein aggregation. E2 treatment did not decrease protein aggregation or improve the heat shock response in either early passage or SEN cells. In summary, cellular senescence in adult human endothelial cells is accompanied by increased oxidative stress and a blunting of proteostasis, and E2 did not mitigate these changes. NEW & NOTEWORTHY Senescent human endothelial cells have a diminished heat shock response and increased protein aggregates. Senescent human endothelial cells have increased basal oxidative stress, which increases protein aggregates. Physiological level of 17β-estradiol did not improve proteostasis in endothelial cells. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/proteostasis-in-senescent-endothelial-cells/ .

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The Heat-Shock Response: Sensing the Stress of Misfolded Proteins

Handbook of Cell Signaling ◽

10.1016/b978-012124546-7/50672-0 ◽

2003 ◽

pp. 269-275 ◽

Cited By ~ 1

Author(s):

Richard I. Morimoto ◽

Ellen A.A. Nollen

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Misfolded Proteins ◽

Shock Response

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Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619234114 ◽

2016 ◽

Vol 114 (2) ◽

pp. E152-E160 ◽

Cited By ~ 21

Author(s):

Matthias C. Truttmann ◽

Xu Zheng ◽

Leo Hanke ◽

Jadyn R. Damon ◽

Monique Grootveld ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Heat Shock ◽

Protein Aggregation ◽

Heat Shock Response ◽

Protein Translation ◽

Cellular Protein ◽

Interacting Protein ◽

Endogenous Protein ◽

Shock Response ◽

Influenza Virus Replication

Protein AMPylation is a conserved posttranslational modification with emerging roles in endoplasmic reticulum homeostasis. However, the range of substrates and cell biological consequences of AMPylation remain poorly defined. We expressed human and Caenorhabditis elegans AMPylation enzymes—huntingtin yeast-interacting protein E (HYPE) and filamentation-induced by cyclic AMP (FIC)-1, respectively—in Saccharomyces cerevisiae, a eukaryote that lacks endogenous protein AMPylation. Expression of HYPE and FIC-1 in yeast induced a strong cytoplasmic Hsf1-mediated heat shock response, accompanied by attenuation of protein translation, massive protein aggregation, growth arrest, and lethality. Overexpression of Ssa2, a cytosolic heat shock protein (Hsp)70, was sufficient to partially rescue growth. In human cell lines, overexpression of active HYPE similarly induced protein aggregation and the HSF1-dependent heat shock response. Excessive AMPylation also abolished HSP70-dependent influenza virus replication. Our findings suggest a mode of Hsp70 inactivation by AMPylation and point toward a role for protein AMPylation in the regulation of cellular protein homeostasis beyond the endoplasmic reticulum.

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