bims-hisfre 2025-06-08 papers

Front Biosci (Landmark Ed). 2025 Apr 30. 30(5): 27324

Molecular Mechanisms and Therapeutic Targeting of Heat Shock Proteins (HSPs) in Cardiovascular Disorders.

Jyoti Upadhyay, Mukesh Nandave, Kamal Y Thajudeen, Summya Rashid, Mohd Nazam Ansari.

Identifying novel biomarkers is a reliable approach to predict and diagnose human diseases as well as manage individual responses to therapeutic drugs. Heat shock proteins (HSPs) are molecular chaperones that play a major role in maintaining protein stability and folding. Many studies suggested their association with multiple types of diseases. HSPs from different categories play different roles; therefore, it is important to identify HSPs and their function to understand their biological functions clearly. This comprehensive review was performed to evaluate the role of HSPs as predictive biomarkers in cardiovascular diseases. The original publications related to HSPs from 2010 to 2024 were identified by using the keywords "heat-shock proteins", "HSP in cardiovascular disorders" and "HSP in atherosclerosis". The regulatory pathways involved in HSPs' functioning are the important points of discussion in this review. HSPs play a critical role in key cellular processes, including apoptosis regulation, protein folding, immune responses, genomic stability, and DNA repair. Aberrant expression of HSPs causes dysregulation of these pathways resulting in the development and progression of diseases. A comprehensive understanding of HSPs in cardiovascular diseases and their associated regulatory pathways can have significant implications for disease intervention, diagnosis, and prognosis. In this review paper, we have highlighted the importance of HSPs as versatile biomarkers and their importance as targets for the therapeutic management of cardiovascular diseases.

Keywords: atherosclerosis; cardiovascular diseases; heat shock protein; predictive biomarker

DOI: https://doi.org/10.31083/FBL27324

FEBS J. 2025 Jun 02.

A guide to heat shock factors as multifunctional transcriptional regulators.

Hendrik S E Hästbacka, Alejandro J Da Silva, Lea Sistonen, Eva Henriksson.

The heat shock factors (HSFs) form a family of transcription factors, which are evolutionarily conserved in eukaryotes. They are best known as transcriptional regulators of molecular chaperone genes, including those encoding heat shock proteins, in response to heat shock and other protein-damaging stresses. Since the discovery of the first HSF and its eponymous role in the heat shock response four decades ago, the currently known HSFs in vertebrates, that is, HSF1-5, HSFX, and HSFY, have been implicated in a wide array of physiological and pathological processes, including organismal development and cancer progression. To date, most studies have focused on individual HSFs, but it is becoming increasingly evident that the role of multiple HSFs and their potential crosstalk should be considered. In this review, we provide a comprehensive overview of the structures, functions, and regulation of the mammalian HSF family members and explore their interplay in biological processes. We highlight recent advancements regarding the roles of HSF family members in viral infection, cell adhesion, and spermatogenesis, and discuss the key questions to be addressed by forthcoming studies in HSF biology.

Keywords: HSE; HSF; HSP; HSR; adhesion; cancer; development; spermatogenesis; stress; transcription

DOI: https://doi.org/10.1111/febs.70139

Nat Commun. 2025 Jun 01. 16(1): 5086

Mechanism of ATP hydrolysis in the Hsp70 BiP nucleotide-binding domain.

Guillaume Mas, Sebastian Hiller.

The 70 kDa heat shock protein (Hsp70) family of molecular chaperones ensures protein biogenesis and homeostasis, driven by ATP hydrolysis. Here, we introduce in-cyclo NMR, an experimental setup that combines high-resolution NMR spectroscopy with an ATP recovery and a phosphate removal system. In-cyclo NMR simultaneously resolves kinetic rates and structural information along functional cycles of ATP-driven molecular machines. We benchmark the method on the nucleotide binding domain (NBD) of the human Hsp70 chaperone BiP. The protein cycles through ATP binding, hydrolysis, and two parallel pathways of product release. We determine the kinetic rates of all eleven underlying elementary reactions and show these to match independent measurements. The two product release pathways regulate the cycle duration dependent on the products concentration. Under physiological conditions, they are both used. The in-cyclo NMR method will serve as a platform for studies of ATP-driven functional cycles at a remarkable level of detail.

DOI: https://doi.org/10.1038/s41467-025-60343-x

Clin Transl Med. 2025 May;15(5): e70346

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome.

Katherine A Glass, Ludovic Giloteaux, Sheng Zhang, Maureen R Hanson.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness characterized by post-exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear. Extracellular vesicles (EVs) play a key role in cell-cell communication and may provide insight into ME/CFS pathophysiology post-exertion. Emerging evidence suggests similarities between ME/CFS and Long COVID, including PEM and overlapping immune and metabolic dysfunctions, highlighting the need for deeper mechanistic understanding.
METHODS: This study explores the EV proteome response to exercise in 10 males with ME/CFS and 12 well-matched sedentary male controls. Participants underwent a maximal cardiopulmonary exercise test, and plasma samples were collected at baseline, 15 min, and 24 h postexercise. EVs were isolated from plasma using size-exclusion chromatography and characterized with nanoparticle tracking analysis. EV protein abundance was quantified with untargeted proteomics (nanoLC-MS/MS). Comprehensive analyses included differential abundance, pathway enrichment, protein-protein interaction networks, and correlations between EV protein dynamics and clinical or exercise physiology data.
RESULTS: ME/CFS patients exhibited many significantly altered EV proteomic responses compared with controls, including downregulation of TCA cycle-related proteins and upregulation of complement system proteins at 15 min postexercise. Changes in proteins involved in protein folding and the endoplasmic reticulum (ER) stress response during recovery were highly correlated with PEM severity, highlighting their potential as therapeutic targets. EV protein changes postexercise were also associated with disease severity and unrefreshing sleep. Correlations between EV protein levels and the exercise parameters VO₂ peak and ventilatory anaerobic threshold were observed in controls but were absent in ME/CFS patients, suggesting disrupted EV-mediated physiological processes.
CONCLUSIONS: ME/CFS patients exhibit a maladaptive EV proteomic response to exercise, characterized by metabolic impairments, immune overactivation, and ER stress response dysregulation. These findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME/CFS.
KEY POINTS: EVs were isolated from plasma of ME/CFS patients and healthy controls at baseline, and 15 min and 24 h postexercise. Untargeted proteomics revealed dysregulation in energy metabolism, the complement system, and the endoplasmic reticulum stress response. Changes in EV protein levels postexercise are associated with post-exertional malaise. These findings suggest promising therapeutic targets for post-exertional malaise and ME/CFS pathophysiology.

Keywords: ME/CFS; chronic fatigue syndrome; complement; exercise; extracellular vesicle cargo; myalgic encephalomyelitis; proteomics

DOI: https://doi.org/10.1002/ctm2.70346

Elife. 2025 Jun 06. pii: RP96675. [Epub ahead of print]13

Clearance of protein aggregates during cell division.

Shoukang Du, Yuhan Wang, Bowen Chen, Shuangshuang Xie, Kuan Yoow Chan, David C Hay, Ting Gang Chew.

Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.

Keywords: ER reorganization; aggregates; cell biology; chaperone; human; mitosis; proteostasis

DOI: https://doi.org/10.7554/eLife.96675

J Cardiovasc Transl Res. 2025 Jun 02.

Extracellular Vesicles as Diagnostic Metrics for Cardiovascular Disease: Where We are and How to Achieve in Clinics.

Yujia Wang, Yingxue Yuan, Junnan Tang.

As one of the leading causes of death globally, early diagnosis and prevention of cardiovascular disease have become the focus of clinical and public health. Extracellular vesicles (EVs) are small, double-layered membrane structures actively secreted by cells and are widely present in body fluids such as blood, urine, and saliva. They carry various bioactive molecules, including proteins and nucleic acids, and are known for their remarkable stability and easy accessibility, making them promising candidates for identifying cardiovascular disease. This review summarizes the applications of EVs in the early diagnosis of cardiovascular disease, explores the potential biomarkers of proteins and RNAs (such as miRNA, lncRNA, and circRNA) contained within EVs, and discusses the prospects and challenges of EV biomarkers in clinical applications.

Keywords: Biomarker; Cardiovascular disease; Diagnosis; Extracellular vesicles

DOI: https://doi.org/10.1007/s12265-025-10629-8