bims-hisfre 2025-05-25 papers

bims-hisfre

Biomed News

on HSF1 and Creatine

Issue of 2025–05–25
ten papers selected by
James Heilman, Oregon Health & Science University

Pharmacological Regulation of Heat Shock Response via Aptamer-Antidote Couple.
Chaperone overexpression boosts heterologous small molecule production in Saccharomyces cerevisiae.
HSP90 and the cancer transcriptome: a comprehensive review of inhibitors and mechanistic insights.
Inhibition of protein or glutamine biosynthesis affect the light-induced dephosphorylation of the SBiP1 chaperone in Symbiodiniaceae.
Problematic issues of ATP synthesis in vivo.
A quantitative comparison of the deleteriousness of missense and nonsense mutations using the structurally resolved human protein interactome.
Peripheral blood heat shock protein 27 correlates with information processing speed and executive function, potentially serving as a marker for mild cognitive impairment in patients with type 2 diabetes mellitus.
From metabolomics to energy balance physiology.
Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.
Symmetric stimulation of Hsp90 catalyzed ATP hydrolysis through enhanced active site gate dynamics.

ACS Chem Neurosci. 2025 May 19.

Pharmacological Regulation of Heat Shock Response via Aptamer-Antidote Couple.

Jaskirat Kaur, Ipsita Roy.

  Heat shock factor 1 (HSF1) orchestrates the cellular heat shock response (HSR) by binding to heat shock elements (HSEs) in the promoters of genes encoding heat shock proteins (HSPs). In a nonstressed state, HSF1 exists in a dormant complex with HSP90 and other chaperones. Upon cellular stress or upon inhibition of HSP90, HSF1 dissociates from the complex and activates the expression of HSPs to mitigate protein misfolding and aggregation. This study explores the potential of RNA aptamers selected against HSP90 to modulate HSF1 activity, with a role in Huntington's disease model characterized by protein aggregation. Selected aptamers disrupted the HSP90-HSF1 interaction, enhancing the binding of HSF1 with HSEs. This upregulated heat shock response (HSR) and reduced aggregation of Q74-huntingtin in Neuro 2a cells with improved cell survival. Designed antidote sequences could reverse the effect of the aptamers on the HSF1-HSE interaction, allowing for fine-tuning of HSR. Chronic activation of stress response pathways is deleterious for cellular fitness. Our findings suggest that coupling an antidote with an aptamer offers a novel therapeutic strategy to regulate cellular proteostasis under disease conditions.

Keywords:  Heat shock proteins; heat shock response; protein aggregation; proteostasis network

DOI:  https://doi.org/10.1021/acschemneuro.4c00865
Microb Cell Fact. 2025 May 19. 24(1): 112

Chaperone overexpression boosts heterologous small molecule production in Saccharomyces cerevisiae.

Andreas M Vestergaard, Wasti Nurani, Paul Cachera, Uffe H Mortensen.

   BACKGROUND: Chaperones play an important role in maintaining cellular proteostasis by mediating protein folding. As a result, chaperone overexpression has been widely used as a tool for enhancing folding and improving production of heterologous proteins in host organisms such as Saccharomyces cerevisiae. In contrast, this strategy has been much less explored for small molecule (SM) production. This is surprising, as SM pathways typically depend on multiple enzymes including large multi-domain synthases or synthetases, which may all benefit from folding assistance to enhance the catalytic power of the pathway.
RESULTS: We have established an S. cerevisiae strain library of 68 strains overexpressing endogenous cytosolic chaperones and a mating-based method that allows the chaperone library to be combined with a query strain that contains the pathway of a desirable SM. Using the small molecule aspulvinone E from Aspergillus terreus as a model compound, we screened the chaperone library for chaperones that improve production of aspulvinone E. Screening of the library identified several chaperones and chaperone combinations that improved aspulvinone E production. Specifically, the combined overexpression of YDJ1 and SSA1 was identified as the best hit in our screen. Subsequently, we demonstrated that overexpression of YDJ1 and SSA1 improved aspulvinone E production by 84% in 1.5 mL scale batch fermentations. The observed increase is likely due to higher levels of the MelA synthetase responsible for aspulvinone E synthesis, as overexpression of YDJ1 and SSA1 increases the amounts of fluorescent MelA-mRFP in cells producing this fusion protein.
CONCLUSION: The endogenous cytosolic chaperone overexpression library and mating based screening method presented in this report constitute a tool allowing for fast and efficient identification of specific chaperones and chaperone combinations that benefit production of a given SM in S. cerevisiae-based cell factories.

Keywords:   Saccharomyces cerevisiae ; Aspulvinone E; Cell factory engineering; Chaperone overexpression; Library screening.; Mating

DOI:  https://doi.org/10.1186/s12934-025-02728-7
Int J Clin Oncol. 2025 May 18.

HSP90 and the cancer transcriptome: a comprehensive review of inhibitors and mechanistic insights.

M V Shahana, Bibha Choudhary.

  This review summarizes the structure, function, expression, and inhibitors of HSP90, the chaperone, in cancers. It systematically investigates the effects of HSP90 inhibitors, including AUY922, B11B021, CCT-018159, D7-gedunin, geldanamycin, and gedunin, across a range of cancer cell lines (HCC151, HT29, MCF7, PC3, VCAP, and A375) and a normal HA1E cell line, using data from the CLUE database. Our analysis reveals that treatment with these HSP90 inhibitors induces significant stress responses in tumor cells, initiating intrinsic and extrinsic apoptotic pathways. The HSP90AA1, HSP90AB1, HSP27, HSP70, VEGF, and NOTCH exhibited notable upregulation at 24 h post-treatment compared to 6 h, indicating a time-dependent increase in cellular stress (heat shock response) and activation of pro-survival signaling mechanisms. Additionally, the study highlights a significant upregulation of immune-related pathways, including those involving IL10, IL3, and IL7, following HSP90 inhibition, indicating that these inhibitors not only directly affect tumor cell viability but also modulate the tumor microenvironment by enhancing immune cell activation and cytokine release. The elevated levels of IL10 point to a dual role, where immune suppression mechanisms are also at play, potentially facilitating immune evasion by the tumor. The findings suggest that HSP90 inhibitors exhibit varying mechanisms of action across different cancer cell lines despite the presence of some common targets. These insights highlight the need for further investigation into the precise mechanisms of HSP90 inhibitors to optimize their therapeutic potential in different cancers.

Keywords:  Combination therapy; Drug resistance; Heat shock protein; Molecular chaperone; Targeted therapy

DOI:  https://doi.org/10.1007/s10147-025-02782-6
Biosci Rep. 2025 May 20. pii: BSR20241085. [Epub ahead of print]

Inhibition of protein or glutamine biosynthesis affect the light-induced dephosphorylation of the SBiP1 chaperone in Symbiodiniaceae.

Raúl Eduardo Castillo-Medina, Tania Islas-Flores, Estefanía Morales-Ruiz, Marco Villanueva.

  Phosphorylation/dephosphorylation is fundamental for transduction of external stimuli into physiological responses. In photosynthetic dinoflagellates Symbiodinium microadriaticum CassKB8, Thr-phosphorylated SBiP1 under dark conditions, undergoes significant dephosphorylation upon light stimuli. We evaluated the effect of protein synthesis inhibitors on light modulated Thr phosphorylation of SBiP1. Inhibition of cytoplasmic protein synthesis by cycloheximide but not of chloroplastic protein synthesis by chloramphenicol, prevented Thr dephosphorylation of the protein under the light. Additionally, inhibition of glutamine synthetase by glufosinate produced a delay in the light induced dephosphorylation of the chaperone. Heat shock reverted the effect in cycloheximide-treated cells suggesting that heat stress overrides the cycloheximide-induced inhibition of SBiP1 dephosphorylation to hypothetically restore chaperone activity. These results suggest that light and stress are critical switches of SBiP1 chaperone activity that function along with common pathways of protein synthesis and ammonia assimilation, and further confirm that the light induced SBiP1 Thr dephosphorylation is independent of photosynthesis.

Keywords:  Symbiodiniaceae; Symbiosis; chaperone; light stimulation; phosphorylation; phototransduction; protein synthesis

DOI:  https://doi.org/10.1042/BSR20241085
Biosystems. 2025 May 19. pii: S0303-2647(25)00103-0. [Epub ahead of print] 105493

Problematic issues of ATP synthesis in vivo.

Viktor V Ivanishchev.

  The work is devoted to description of processes that provide fundamental conditions for ATP synthesis in vivo. The work presents information on the basis of which a general fundamental picture of formation of electrochemical gradient on the mitochondrial (or chloroplast) membrane and its use for ATP-synthase operation is described. An attempt was made to explain the order of appearance of electrical and chemical gradients, as well as the feedback between electrical and chemical components of the driving force in mitochondria and chloroplasts based on Nath's two-ion theory. The results of the analysis allowed us to conclude that a series of sequential events (which are separated in time and space) is necessary for ATP synthesis in vivo, namely: formation of electrical potential, formation of chemical potential, their use for ATP synthase operation. The electrical component is formed due to light energy (chloroplast) or metabolite-associated processes (mitochondria) by pumping of H+ by the electron transport chain. Formation of chemical gradients occur only upon collapse of the electrical gradient by counterion translocation. As a result of their interaction, a driving force (plus change in the conformation of membrane components) is formed on the membrane, which makes ATP-synthase work. The reasons for significant differences in the values of the chemical and electrical components of the gradient on the membranes of mitochondria and chloroplasts are shown (explained). Analysis of the active transport of metabolites from the mitochondria allows us to conclude that it is possible to "break" the concentration flow of Krebs cycle metabolites into mitochondria in vivo, which can be maintained by cytoplasmic malate.

Keywords:  ATP synthesis; chloroplast; electrochemical gradient; electron transport chain; metabolites; mitochondria

DOI:  https://doi.org/10.1016/j.biosystems.2025.105493
Protein Sci. 2025 Jun;34(6): e70155

A quantitative comparison of the deleteriousness of missense and nonsense mutations using the structurally resolved human protein interactome.

Ting-Yi Su, Yu Xia.

  The complex genotype-to-phenotype relationships in Mendelian diseases can be elucidated by mutation-induced disturbances to the networks of molecular interactions (interactomes) in human cells. Missense and nonsense mutations cause distinct perturbations within the human protein interactome, leading to functional and phenotypic effects with varying degrees of severity. Here, we structurally resolve the human protein interactome at atomic-level resolutions and perform structural and thermodynamic calculations to assess the biophysical implications of these mutations. We focus on a specific type of missense mutation, known as "quasi-null" mutations, which destabilize proteins and cause similar functional consequences (node removal) to nonsense mutations. We propose a "fold difference" quantification of deleteriousness, which measures the ratio between the fractions of node-removal mutations in datasets of Mendelian disease-causing and non-pathogenic mutations. We estimate the fold differences of node-removal mutations to range from 3 (for quasi-null mutations with folding ΔΔG ≥2 kcal/mol) to 20 (for nonsense mutations). We observe a strong positive correlation between biophysical destabilization and phenotypic deleteriousness, demonstrating that the deleteriousness of quasi-null mutations spans a continuous spectrum, with nonsense mutations at the extreme (highly deleterious) end. Our findings substantiate the disparity in phenotypic severity between missense and nonsense mutations and suggest that mutation-induced protein destabilization is indicative of the phenotypic outcomes of missense mutations. Our analyses of node-removal mutations allow for the potential identification of proteins whose removal or destabilization lead to harmful phenotypes, enabling the development of targeted therapeutic approaches, and enhancing comprehension of the intricate mechanisms governing genotype-to-phenotype relationships in clinically relevant diseases.

Keywords:  Mendelian diseases; deleteriousness of mutations; functional consequences; genotype‐to‐phenotype relationships; human genetic variants; human protein interactome; interactome disruptions; missense and nonsense mutations; protein stability; structural systems biology

DOI:  https://doi.org/10.1002/pro.70155
Diabetol Metab Syndr. 2025 May 24. 17(1): 167

Peripheral blood heat shock protein 27 correlates with information processing speed and executive function, potentially serving as a marker for mild cognitive impairment in patients with type 2 diabetes mellitus.

Shufang Yang, Haoqiang Zhang, Wenwen Zhu, Tong Niu, Huzaifa Fareeduddin Mohammed Farooqui, Jue Wang, Mingyue Yang, Enlin Liu, Shaohua Wang.

   BACKGROUND AND AIMS: Previous study found that interleukin 1β (IL-1β) is associated with diabetic cognitive dysfunction. Heat shock protein 27 (HSP27) is one of the factors related to IL-1β associated inflammation. Here, we aim to investigate the role of HSP27 in mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).
MATERIALS AND METHODS: In this study, individuals with T2DM with and without MCI were recruited and categorized into Control and MCI groups. Plasma HSP27 levels were assessed and compared between the Control and MCI groups. Furthermore, the relationship between HSP27 and diabetic dysfunction was elucidated through association and regression analyses. Finally, diagnostic values were determined using ROC curves.
RESULTS: In humans, individuals with T2DM and MCI exhibit decreased levels of HSP27 compared to those without MCI. Notably, the levels of HSP27 are associated with neuropsychological test scores that reflect cognitive preferences. Additionally, decreased HSP27 levels serve as one of the risk factors for MCI in T2DM patients (OR = 0.355, P = 0.002). Moreover, there is a defined cut-off point for HSP27 in diagnosing MCI, set at 3.51 pg/ml, with a sensitivity of 47.2%, a specificity of 94.4%, and an area under the curve (AUC) of 0.695.
CONCLUSIONS: Generally speaking, HSP27 is linked to cognitive decline in individuals with T2DM. Decreased levels of HSP27 in plasma are identified as both a risk factor for MCI and a potential diagnostic biomarker for MCI in patients with T2DM. The diagnostic value of HSP27 in MCI is primarily reflected in its demonstrated true negative rate.

Keywords:  Heat shock protein 27; Mild cognitive impairment; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1186/s13098-025-01747-z
Adv Genet. 2025 ;pii: S0065-2660(24)00038-5. [Epub ahead of print]113 102-145

From metabolomics to energy balance physiology.

María José Ortuño Romero, Daxiang Na.

  Omics technologies are transforming our understanding of disease mechanisms and reshaping clinical practice. By enabling high-throughput, unbiased data collection at various molecular levels - including genes (genomics), mRNA (transcriptomics), proteins (proteomics), and metabolites (metabolomics) - omics approaches offer a comprehensive view of biological states in both health and disease. Among these, metabolomics has emerged as a pivotal tool, rapidly evolving beyond diagnostics to become a cutting-edge technique for pinpointing metabolites that regulate key physiological processes. This chapter reviews the advances in metabolomics, its integration with other omics approaches, and its applications, particularly emphasizing energy homeostasis. By incorporating metabolomic insights into physiology, we move closer to an integrative understanding of biological systems, laying the groundwork for novel therapies to combat obesity and related metabolic disorders.

Keywords:  Lipidomics; Metabolomics; Obesity; Omics Integration

DOI:  https://doi.org/10.1016/bs.adgen.2024.11.001
Front Cell Dev Biol. 2025 ;13 1538377

Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.

Raffaella Bonavita, Fulvia Vitale, Luigi Vittorio Verdicchio, Sarah V Williams, Maria Gabriella Caporaso, Angeleen Fleming, Maurizio Renna.

  Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's and Huntington's diseases as well as ataxias and fronto-temporal disorders are all characterized by the progressive accumulation of protein aggregates (amyloids) into inclusions bodies. In addition, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of some of these disease-relevant proteins to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the role of small heat shock proteins (sHSPs) and autophagy in cellular quality control and turn-over of the major aggregation-prone proteins associated to neurodegenerative disorders. We also highlight the advanced research progress on mechanisms regulating unconventional secretion, secretory autophagy and EVs biogenesis and their contribution in the pathological processes underlining these diseases. Finally, we outline the latest research on the roles of EVs in neurodegenerative diseases and their potential diagnostic and therapeutic significance for the treatment of these clinically relevant conditions.

Keywords:  autophagy; extracellular vesicles and exosomes; neurodegenerative diseases; protein misfolding; protein oligomerization and aggregation; small heat shock proteins; unconventional protein secretion

DOI:  https://doi.org/10.3389/fcell.2025.1538377
J Biol Chem. 2025 May 21. pii: S0021-9258(25)02112-X. [Epub ahead of print] 110262

Symmetric stimulation of Hsp90 catalyzed ATP hydrolysis through enhanced active site gate dynamics.

Breanna Magnan, Thomas Dumont, Suad Rashid, Paul LaPointe, Leo Spyracopoulos.

  Heat shock protein 90 (Hsp90) is a vital molecular chaperone that is essential for activating a diverse array of regulatory proteins through an ATP-dependent clamping cycle. The Hsp90 clamping cycle is driven by large-amplitude conformational changes within the N-terminal ATPase domain, including the release of an autoinhibitory N-terminal β-strap followed by a less well-characterized ATP gate rearrangement involving N-terminal helix 1. Here, we employed a combination of 19F nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and ATPase assays to examine the effects of targeted β-strap and helix 1 mutations. Our findings reveal that targeted disruption of helix 1 packing against the ATPase domain accelerates clamp closure, symmetrically enhancing ATP hydrolysis for both subunits of the Hsp90 dimer, whereas activation by the Aha1 cochaperone is disrupted. Decreasing the energy barrier associated with helix 1 release is a key step in modulating the energy landscape that governs the dynamics of the Hsp90 clamping cycle.

Keywords:  (19)F NMR; ATPase; chaperone; enzyme kinetics; heat shock protein 90 (Hsp90); molecular chaperone; molecular dynamics; protein dynamics

DOI:  https://doi.org/10.1016/j.jbc.2025.110262