Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

Edkins, Adrienne L.; Price, John T.; Pockley, A. Graham; Blatch, Gregory L.

doi:10.1098/rstb.2016.0521

Cited by 52 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The Hsp90 dependent regulation offers an opportunity for SIRT1 function to integrate inputs both from proteostasis as well as from the ATP level. Likewise, efficiency of SIRT1 activators might require abundant Hsp90 and co-chaperone capacity, which decreases during aging but can be upregulated by chaperone inducers [ 60 ]. Such a combination therapy might benefit several age-related metabolic and protein misfolding diseases, where SIRT1 activation holds great promise [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

Nguyen

Somogyvári

Sőti

2018

IJMS

View full text Add to dashboard Cite

Sirtuin 1 (SIRT1) othologs are ubiquitous NAD+-dependent deacetylases that act as nutrient sensors and modulate metabolism and stress responses in diverse organisms. Both mammalian SIRT1 and Caenorhabditis elegans SIR-2.1 have been implicated in dietary restriction, longevity, and healthspan. Hsp90 is an evolutionarily conserved molecular chaperone that stabilizes a plethora of signaling ’client’ proteins and regulates fundamental biological processes. Here we report that Hsp90 is required for conformational stabilization of SIRT1 and SIR-2.1. We find that inhibition of Hsp90 by geldanamycin (GA) induces the depletion of mammalian SIRT1 protein in a concentration and time dependent manner in COS-7 and HepG2 cells. In contrast to SIRT1, SIRT2 level remains unchanged by GA treatment, reflecting a specific Hsp90 SIRT1 interaction. Hsp90 inhibition leads to the destabilization and proteasomal degradation of SIRT1. Moreover, we observe a GA-sensitive physical interaction between SIRT1 and Hsp90 by immunoprecipitation. We also demonstrate that hsp-90 gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in C. elegans. Our findings identify metazoan SIRT1 orthologs as Hsp90 clients and reveal a novel crosstalk between the proteostasis and nutrient signaling networks, which may have implications in various age related diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

Nguyen

Somogyvári

Sőti

2018

IJMS

View full text Add to dashboard Cite

show abstract

“…Heat shock proteins (Hsps) are highly conserved and ubiquitously expressed proteins that normally act as molecular chaperones which help in the maintenance of protein homeostasis by assisting their folding processes [ 1 , 2 ]. Their involvement in proper protein folding, prevention of protein aggregation and apoptosis is of great importance for cellular function, especially when cells are exposed to stressful conditions [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Association of Plasma Heat Shock Protein 70 with Disease Severity, Smoking and Lung Function of Patients with Chronic Obstructive Pulmonary Disease

Hlapčić

Hulina

Rajković

et al. 2020

JCM

View full text Add to dashboard Cite

Extracellular heat shock protein 70 (eHsp70) might modulate immune responses in chronic obstructive pulmonary disease (COPD). The aim of the study was to explore eHsp70 concentration in stable COPD, its association with disease severity and smoking status as well as its diagnostic performance in COPD assessment. Plasma samples were collected from 137 COPD patients and 95 healthy individuals, and concentration of eHsp70 was assessed by commercially available enzyme-linked immunosorbent assay (ELISA) kit (Enzo Life Science, Farmingdale, NY, USA). COPD patients were subdivided regarding airflow obstruction severity and symptoms severity according to the Global Initiative for COPD (GOLD) guidelines. eHsp70 concentration increased in COPD patients when compared to controls and increased with the severity of airflow limitation as well as symptoms burden and exacerbation history. eHsp70 concentration did not differ among COPD patients based on smoking status, yet it increased in healthy smokers compared to healthy nonsmokers. In addition, eHsp70 negatively correlated with lung function parameters forced expiratory volume in one second (FEV1) and FEV1/ forced vital capacity (FVC), and positively with COPD multicomponent indices BODCAT (BMI, airflow obstruction, dyspnea, CAT score), BODEx (BMI, airflow obstruction, dyspnea, previous exacerbations), CODEx (Charlson’s comorbidity index, airflow obstruction, dyspnea, previous exacerbations) and DOSE (dyspnea, airflow obstruction, smoking status, previous exacerbations) With great predictive value (OR = 7.63) obtained from univariate logistic regression, eHsp70 correctly classified 76% of cases. eHsp70 is associated with COPD prediction and disease severity and might have the potential for becoming an additional biomarker in COPD assessment.

show abstract

“…One of the main roles associated with the HSPs is to support protein maintenance, including assisting the proper folding of newly synthesized proteins, refolding and clearance of misfolded and/or aggregated proteins, and participating in the membrane translocation of secretory proteins [24]. As the folding, maintenance, and degradation of proteins are key requirements for cell homeostasis, alterations in the HSR and the associated functions of HSPs have been linked to chronic diseases, such as AD and T2D.…”

Section: Introductionmentioning

confidence: 99%

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Rowles

Keane

Heck

et al. 2020

IJMS

View full text Add to dashboard Cite

Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD.

show abstract

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

Cited by 52 publications

References 50 publications

Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

Association of Plasma Heat Shock Protein 70 with Disease Severity, Smoking and Lung Function of Patients with Chronic Obstructive Pulmonary Disease

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Contact Info

Product

Resources

About