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Homeostatic maintenance of the physicochemical properties of cellular membranes is essential for life. In yeast, trehalose accumulation and lipid remodeling enable rapid adaptation to perturbations, but their crosstalk was not investigated. Here we report about the first in-depth, mass spectrometry-based lipidomic analysis on heat-stressed Schizosaccharomyces pombe mutants which are unable to synthesize (tps1Δ) or degrade (ntp1Δ) trehalose. Our experiments provide data about the role of trehalose as a membrane protectant in heat stress. We show that under conditions of trehalose deficiency, heat stress induced a comprehensive, distinctively high-degree lipidome reshaping in which structural, signaling and storage lipids acted in concert. In the absence of trehalose, membrane lipid remodeling was more pronounced and increased with increasing stress dose. It could be characterized by decreasing unsaturation and increasing acyl chain length, and required de novo synthesis of stearic acid (18:0) and very long-chain fatty acids to serve membrane rigidification. In addition, we detected enhanced and sustained signaling lipid generation to ensure transient cell cycle arrest as well as more intense triglyceride synthesis to accommodate membrane lipid-derived oleic acid (18:1) and newly synthesized but unused fatty acids. We also demonstrate that these changes were able to partially substitute for the missing role of trehalose and conferred measurable stress tolerance to fission yeast cells.

The plasma membrane (PM) of eukaryotic cells plays a key role in the response to stress, acting as the first line of defense against environmental changes and protecting cells against intracellular perturbations. In this work, we explore how membrane-bound chaperones and membrane lipid domains work together to shape plasma membrane properties—a partnership we refer to as the “epichaperome–plasma membrane lipid axis.” This axis influences membrane fluidity, curvature, and domain organization, which in turn shapes the spatial and temporal modulation of signaling platforms and pathways essential for maintaining cellular integrity and homeostasis. Changes in PM fluidity can modulate the activity of ion channels, such as transient receptor potential (TRP) channels. These changes also affect processes such as endocytosis and mechanical signal transduction. The PM proteome undergoes rapid changes in response to membrane perturbations. Among these changes, the expression of heat shock proteins (HSPs) and their accumulation at the PM are essential mediators in regulating the physical state and functional properties of the membrane. Because of the pivotal role in stress adaptation, HSPs influence a wide range of cellular processes, which we grouped into three main categories: (i) mechanistic insights, differentiating in vitro (liposome, reconstituted membrane systems) and in vivo evidence for HSP-PM recruitment; (ii) functional outputs, spanning how ion channels are affected, changes in membrane fluidity, transcytosis, and the process of endocytosis and exosome release; and (iii) pathological effects, focusing on how rewired lipid–chaperone crosstalk in cancer drives resistance to drugs through altered membrane composition and signaling. Finally, we highlight Membrane Lipid Therapy (MLT) strategies, such as nanocarriers targeting specific PM compartments or small molecules that inhibit HSP recruitment, as promising approaches to modulate the functional stability of epichaperome assembly and membrane functionality, with profound implications for tumorigenesis.

Epidermal Growth Factor Receptor (EGFR) signaling plays a central role in cell proliferation, migration, and survival. Emerging evidence suggests a connection between ADP-ribosylation and EGFR regulation. Previous studies implicated PARP’s role in EGFR signaling, but the participation of ADP(ribosyl)hydrolases in it, that can revert their enzymatic modifications, still remained elusive. The role of TARG1, a macrodomain-containing hydrolase, that has been implicated in RNA metabolism, and cellular stress response, but was not studied in EGFR signaling before. Here, we investigate the impact of TARG1 depletion in U2-OS osteosarcoma cells using knockout (KO) and knockdown (KD) models. We find that TARG1 loss reduces both EGFR protein and mRNA levels. Our results show increased mRNA turnover and altered RNA distribution and translation in TARG1 KO cells, suggesting that TARG1 influences RNA metabolism and translational regulation. Notably, TARG1-deficient cells exhibit heightened sensitivity to MEK1/2 inhibition, indicating potential crosstalk between TARG1 and the Ras/MEK/ERK pathway. These findings suggest that TARG1, and possibly ADP-ribosylation, regulate EGFR expression and translation through RNA biogenesis-mediated mechanisms, highlighting its potential role in cancer cell signaling and survival.

Editorial on the Research Topic Novel insights into the modulation of protein function by lipids and membrane organization Although the plasma membrane was originally thought to solely represent a passive diffusion barrier separating the intracellular and extracellular spaces, a growing body of evidence supports the active contribution of lipids and membrane organization to regulating the structure and function of transmembrane proteins. Furthermore, the tendency of biological membranes to segregate laterally into dynamic nano- and microdomains such as cholesterol-enriched lipid rafts and ceramide platforms, and their changes in response to altered lipid composition, add a further level of complexity to the active modulatory role of lipids in the functional regulation of proteins. After summarizing related literature cryo-EM data, the authors introduced a simplified computational model of the endoplasmic reticulum-localized sphingolipid flux, and analyzed the energetic contribution of single residues to ceramide binding by calculating the docking score and the predicted binding free energy for mutant SPT-ORMDL complexes, which, while not being validated experimentally in the study, are in agreement with recently published experimental data. Mechanosensitive ion channels, which play a substantial role in endothelial mechanotransduction and thus blood pressure regulation, are activated by mechanical forces, such as shear stress, a frictional force generated by the blood flow and membrane tension generated by stretch (Beverley et al., 2025) and their endothelial stiffening-induced functional alterations may contribute to cardiovascular disease and aging (Aguilar et al., 2022).

Cell membranes actively participate in stress sensing and signalling. Here we present the first in-depth lipidomic analysis to characterize alterations in the fission yeast Schizosaccharomyces pombe in response to mild heat stress (HS). The lipidome was assessed by a simple one-step methanolic extraction. Genetic manipulations that altered triglyceride (TG) content in the absence or presence of HS gave rise to distinct lipidomic fingerprints for S. pombe. Cells unable to produce TG demonstrated long-lasting growth arrest and enhanced signalling lipid generation. Our results reveal that metabolic crosstalk between membrane and storage lipids facilitates homeostatic maintenance of the membrane physical/chemical state that resists negative effects on cell growth and viability in response to HS. We propose a novel stress adaptation mechanism in which heat-induced TG synthesis contributes to membrane rigidization by accommodating unsaturated fatty acids of structural lipids, enabling their replacement by newly synthesized saturated fatty acids.

Background Obesity is a global health challenge that can lead to various complications, such as metabolic syndrome, diabetes mellitus, and cardiovascular diseases. Heat shock proteins are evolutionarily conserved chaperones that help maintain cellular protein homeostasis. Their expression is dysregulated in various chronic diseases, including diabetes mellitus and hyperlipidemia, and they also regulate inflammatory processes. Therefore, the present study aimed to investigate the effects of a small heat shock protein, HSPB1, on the comorbidities and complications of obesity in a transgenic mouse model. Methods Male and female human apolipoprotein B-100 (APOB) transgenic mice fed with a high-fat diet (HFD) from months 3–10 of age were used as a model of metabolic syndrome (MetS). To study whether HSPB1 influences the development of MetS, APOB animals were crossed with HSPB1-overexpressing mice. Age and sex-matched wild-type and human HSPB1-overexpressing mice were used as controls. Changes in cardiac morphology and function were assessed by transthoracic echocardiography at month 9. At month 10, serum triglyceride and cholesterol concentrations were determined by enzymatic colorimetric assays. Pathological changes in the liver were studied on hematoxylin–eosin-stained sections. Expression levels of genes involved in inflammation and metabolism were measured by quantitative real-time polymerase chain reaction in the liver, left ventricle, and visceral white adipose tissue (vWAT). Results The body weight and serum LDL-cholesterol levels were significantly higher in the APOB animals than in the wild-type mice in both sexes. Notably, HSPB1 overexpression further increased weight gain in female APOB animals. Conversely, in APOB males, HSPB1 overexpression decreased LDL-cholesterol levels without significantly affecting body weight. Furthermore, in APOB females, HSPB1 overexpression elevated Fgf-21 expression in the vWAT, restored Lpl levels, and reduced the expression of several cytokines in the liver. APOB males developed left ventricular hypertrophy (LVH) with diastolic dysfunction. HSPB1 overexpression induced LVH without cardiac dysfunction in the wild-type animals. Conclusions Both sexes of APOB animals developed MetS. APOB males presented LVH with preserved ejection fraction (EF); however, APOB females showed enlarged left ventricular end-systolic volume (LVESV). In APOB animals, HSPB1 overexpression exerted a sex-dependent influence on obesity-related alterations, including weight gain, hypercholesterolemia, and hepatic and vWAT gene expression. Highlights • Overexpression of human HSPB1 led to further weight gain in HFD-fed APOB-100 females, while the body weights of HFD-fed APOB-100 males were unaffected by human HSPB1. • Human HSPB1 overexpression significantly decreased the LDL-cholesterol levels in HFD-fed APOB-100 males. • mRNA level of fibroblast growth factor 21 was elevated in the vWAT of HFD-fed APOB-100 females in response to human HSPB1 overexpression. • Increased gene expression level of lipoprotein lipase was restored by human HSPB1 overexpression in the liver of HFD-fed APOB-100 females. • Overexpression of human HSPB1 failed to restore hyperlipidemia-related cardiac morphological alterations found in HFD-fed APOB-100 males, while it induced LVH in the wild-type animals of both sexes. Plain English Summary Representing the primary risk factor for several chronic diseases, including non-alcoholic fatty liver disease, type 2 diabetes mellitus, and cardiovascular diseases, obesity is a global health challenge nowadays. Cells defend themselves against various stress and disease conditions by inducing a stress response characterized by the activation of heat shock proteins. However, the levels of these proteins and the inducibility of the cellular stress response are altered in chronic metabolic diseases, such as diabetes or hyperlipidemia. Here, we aimed to analyze whether a small molecular weight heat shock protein, HSPB1, has an effect on MetS using a mouse model. We found that HSPB1 overexpression led to a further increase in weight gain and blood LDL-cholesterol concentration in female disease model animals. Conversely, in males, HSPB1 overexpression led to a decrease in LDL cholesterol levels without any significant impact on body weight. However, despite the higher body weight, none of the investigated comorbidities, such as inflammation, hepatic steatosis, or cardiac dysfunction, were worsened in the disease model females in response to HSPB1 overexpression, supported by the sex-specific alterations in the gene expression pattern in these tissues. These results suggest that HSPB1 may have a complex regulatory role in obesity-related comorbidities. Although the restoration of the heat shock response and levels of heat shock proteins may be an effective therapeutic strategy in metabolic disorders, it is important to consider sex-based differences to ensure optimal outcomes.

We investigated whether the elimination of two major enzymes responsible for triacylglycerol synthesis altered the structure and physical state of organelle membranes under mild heat shock conditions in the fission yeast, Schizosaccharomyces pombe. Our study revealed that key intracellular membrane structures, lipid droplets, vacuoles, the mitochondrial network, and the cortical endoplasmic reticulum were all affected in mutant fission yeast cells under mild heat shock but not under normal growth conditions. We also obtained direct evidence that triacylglycerol-deficient cells were less capable than wild-type cells of adjusting their membrane physical properties during thermal stress. The production of thermoprotective molecules, such as HSP16 and trehalose, was reduced in the mutant strain. These findings suggest that an intact system of triacylglycerol metabolism significantly contributes to membrane protection during heat stress.

Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elements—neuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the postsynaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation—a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide break-through therapy for dementia-associated disease.

Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen.

IntroductionThe burden of type 2 diabetes mellitus (T2DM) is increasing worldwide. Heat therapy has been found effective in improving glycaemic control. However, to date, there is a lack of randomised controlled studies investigating the efficacy of heat therapy in T2DM. Therefore, we aim to investigate whether heat therapy with natural thermal mineral water can improve glycaemic control in patients with T2DM.Methods and analysisThe HEAT therapy in patiEnts with type 2 Diabetes mellitus (HEATED) Study is a single-centre, two-arm randomised controlled trial being conducted at Harkány Thermal Rehabilitation Centre in Hungary. Patients with T2DM will be randomly assigned to group A (bath sessions in 38°C natural thermal mineral water) and group B (baths in thermoneutral water (30°C–32°C)). Both groups will complete a maximum of 5 weekly visits, averaging 50–60 visits over the 12-week study. Each session will last 30 min, with a physical check-up before the bath. At baseline, patients’ T2DM status will be investigated thoroughly. Possible microvascular and macrovascular complications of T2DM will be assessed with physical and laboratory examinations. The short form-36 questionnaire will assess the quality of life. Patients will also be evaluated at weeks 4, 8 and 12. The primary endpoint will be the change of glycated haemoglobin from baseline to week 12. An estimated 65 patients will be enrolled per group, with a sample size re-estimation at the enrolment of 50% of the calculated sample size.Ethics and disseminationThe study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (818-2/2022/EÜIG). Written informed consent is required from all participants. We will disseminate our results to the medical community and will publish our results in peer-reviewed journals.Trial registration numberClinicalTrials.gov, NCT05237219.