Protein Homeostasis as a Therapeutic Target for Diseases of Protein Conformation

Calamini, Barbara; Morimoto, Richard I.

doi:10.2174/1568026611212220014

Cited by 87 publications

(59 citation statements)

References 164 publications

(196 reference statements)

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“…The likelihood of developing diseases of protein dysfunction, such as neurodegenerative disorders, is increased upon aging, due in part to the decline of the HSR during the aging process (Ben‐Zvi, Miller, & Morimoto, 2009; Labbadia & Morimoto, 2015). Activators of the HSR have been suggested as possible therapeutic strategies for diseases of aging (Balch, Morimoto, Dillin, & Kelly, 2008; Calamini & Morimoto, 2012; Neef, Turski, & Thiele, 2010; Westerheide & Morimoto, 2005), but many of the small molecules known to modulate HSF1 activity have cytotoxicity and poor bioavailability. Our data suggest that modulating SIR‐2.1 activity may prevent an age‐associated decline in the HSR and may prevent polyglutamine aggregation in a C. elegans Huntington's disease model.…”

Section: Discussionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat‐shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA‐bound state of HSF1 through deacetylation of the DNA‐binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell‐cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF‐1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR‐1. This negative regulation requires the SIRT1 homolog SIR‐2.1. In addition, knockdown of CCAR‐1 via ccar‐1 RNAi works through SIR‐2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.

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Section: Discussionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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“…Stress-inducible phosphorylation of HSF1, or hyperphosphorylation, is one of the most prominent modifications, coinciding with the acquisition of its transactivation capacity (30,(37)(38)(39)(40). However, despite a wealth of studies on the role of single phosphorylation sites (29,30,34,(40)(41)(42), no direct link between hyperphosphorylation and HSF1 activation has been established.Many pathological conditions, such as metabolic disorders, cancers, and neurodegenerative diseases, are associated with either increased or decreased activity of molecular chaperones (43,44). Hence, modulating the heat shock response by altering HSF1 activity has been proposed as a potential therapeutic approach …”

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confidence: 99%

“…Many pathological conditions, such as metabolic disorders, cancers, and neurodegenerative diseases, are associated with either increased or decreased activity of molecular chaperones (43,44). Hence, modulating the heat shock response by altering HSF1 activity has been proposed as a potential therapeutic approach (44)(45)(46).…”

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Uncoupling Stress-Inducible Phosphorylation of Heat Shock Factor 1 from Its Activation

Budzyński

Puustinen

Joutsen

et al. 2015

Molecular and Cellular Biology

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bIn mammals the stress-inducible expression of genes encoding heat shock proteins is under the control of the heat shock transcription factor 1 (HSF1). Activation of HSF1 is a multistep process, involving trimerization, acquisition of DNA-binding and transcriptional activities, which coincide with several posttranslational modifications. Stress-inducible phosphorylation of HSF1, or hyperphosphorylation, which occurs mainly within the regulatory domain (RD), has been proposed as a requirement for HSF-driven transcription and is widely used for assessing HSF1 activation. Nonetheless, the contribution of hyperphosphorylation to the activity of HSF1 remains unknown. In this study, we generated a phosphorylation-deficient HSF1 mutant (HSF1⌬ϳPRD), where the 15 known phosphorylation sites within the RD were disrupted. Our results show that the phosphorylation status of the RD does not affect the subcellular localization and DNA-binding activity of HSF1. Surprisingly, under stress conditions, HSF1⌬ϳPRD is a potent transactivator of both endogenous targets and a reporter gene, and HSF1⌬ϳPRD has a reduced activation threshold. Our results provide the first direct evidence for uncoupling stress-inducible phosphorylation of HSF1 from its activation, and we propose that the phosphorylation signature alone is not an appropriate marker for HSF1 activity.T he heat shock response, as characterized by inducible expression of heat shock proteins (Hsps), is an ancient, evolutionarily conserved mechanism that protects cells from various proteotoxic insults, including exposures to elevated temperatures, heavy metals, proteasome inhibition, and oxidative stress (1). Hsps function as molecular chaperones, bind to misfolded proteins, facilitate their refolding or direct them to degradation, and block the formation of protein aggregates (2, 3). The heat shock response is controlled by heat shock transcription factors (HSFs) (4). In vertebrates, four HSFs (HSF1 to HSF4) have been found, whereas yeasts, flies, and nematodes have only a single HSF. HSFs bind DNA at evolutionarily well-conserved sequences, consisting of inverted nGAAn repeats, called heat shock elements (5-8). HSF1 is considered the master regulator of the heat shock response in mammals, since mice lacking HSF1 are unable to induce Hsp expression upon exposure to protein-damaging stress (9, 10). Besides controlling the stress-inducible expression of Hsps, HSF1 plays a role in development (10-12), life span regulation (13-15), immune responses (16), and the circadian cycle (17). In addition, HSF1 is a well-recognized transcriptional regulator in malignant human cancers (18)(19)(20).The HSF1 protein is composed of five distinguishable functional domains (see Fig. 1A). The DNA-binding domain (DBD) is located at the N terminus (21), whereas the transactivation domain (TAD) resides in the C terminus (22). A unique requirement for HSF1 activation is the process of trimerization through an intermolecular interaction of leucine-zipper-like heptad repeat domains (HR-A/B) between HSF1...

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“…A better understanding of this process may enable the development of new approaches to treat misfolding and aggregation diseases. Guiding misfolded proteins towards beneficial PQC compartments, or away from potentially detrimental ones may represent the next direction of therapeutic design in the field of protein misfolding disorders (reviewed in [59,62]). Thus, it remains critical to understand the cell biology involved in PQC body formation in order to design appropriate therapeutic approaches for the wide range of misfolding diseases.…”

Section: Discussionmentioning

confidence: 99%

Sorting out the trash: the spatial nature of eukaryotic protein quality control

Sontag

Vonk

Frydman

2014

Current Opinion in Cell Biology

146

141

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Failure to maintain protein homeostasis is associated with aggregation and cell death, and underies a growing list of pathologies including neurodegenerative diseases, aging and cancer. Misfolded proteins can be toxic and interfere with normal cellular functions, particularly during proteotoxic stress. Accordingly, molecular chaperones, the ubiquitin-proteasome system and autophagy together promote refolding or clearance of misfolded proteins. Here we discuss emerging evidence that the pathways of protein quality control (PQC) are intimately linked to cell architecture, and sequester proteins into spatially and functionally distinct PQC compartments. This sequestration serves a number of functions, including enhancing the efficiency of quality control; clearing the cellular milieu of potentially toxic species and facilitating asymmetric inheritance of damaged proteins to promote rejuvenation of daughter cells.

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Protein Homeostasis as a Therapeutic Target for Diseases of Protein Conformation

Cited by 87 publications

References 164 publications

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

Uncoupling Stress-Inducible Phosphorylation of Heat Shock Factor 1 from Its Activation

Sorting out the trash: the spatial nature of eukaryotic protein quality control

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