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Cell Reports Nov 2023Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase...
Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.
Topics: Peptide Hydrolases; Calmodulin; Saccharomyces cerevisiae Proteins; Caspases; Saccharomyces cerevisiae; Molecular Chaperones
PubMed: 37938971
DOI: 10.1016/j.celrep.2023.113372 -
International Journal of Molecular... Jul 2023Atherosclerosis is a major global health problem. Being a harbinger of a large number of cardiovascular diseases, it ultimately leads to morbidity and mortality. At the... (Review)
Review
Atherosclerosis is a major global health problem. Being a harbinger of a large number of cardiovascular diseases, it ultimately leads to morbidity and mortality. At the same time, effective measures for the prevention and treatment of atherosclerosis have not been developed, to date. All available therapeutic options have a number of limitations. To understand the mechanisms behind the triggering and development of atherosclerosis, a deeper understanding of molecular interactions is needed. Heat shock proteins are important for the normal functioning of cells, actively helping cells adapt to gradual changes in the environment and survive in deadly conditions. Moreover, multiple HSP families play various roles in the progression of cardiovascular disorders. Some heat shock proteins have been shown to have antiatherosclerotic effects, while the role of others remains unclear. In this review, we considered certain aspects of the antiatherosclerotic activity of a number of heat shock proteins.
Topics: Humans; Heat-Shock Proteins; Atherosclerosis; Cardiovascular Diseases; HSP70 Heat-Shock Proteins
PubMed: 37511509
DOI: 10.3390/ijms241411750 -
Cellular & Molecular Biology Letters Jan 2024Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes of death in patients with sepsis. SCM's pathogenesis is...
New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation.
BACKGROUND
Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes of death in patients with sepsis. SCM's pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, the specific mechanisms and their intricate interactions in SCM remain unclear. This study employed bioinformatics analysis and drug discovery approaches to identify the regulatory molecules, distinct functions, and underlying interactions of mitochondrial metabolism and immune microenvironment, along with potential interventional strategies in SCM.
METHODS
GSE79962, GSE171546, and GSE167363 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and module genes were identified using Limma and Weighted Correlation Network Analysis (WGCNA), followed by functional enrichment analysis. Machine learning algorithms, including support vector machine-recursive feature elimination (SVM-RFE), least absolute shrinkage and selection operator (LASSO) regression, and random forest, were used to screen mitochondria-related hub genes for early diagnosis of SCM. Subsequently, a nomogram was developed based on six hub genes. The immunological landscape was evaluated by single-sample gene set enrichment analysis (ssGSEA). We also explored the expression pattern of hub genes and distribution of mitochondria/inflammation-related pathways in UMAP plots of single-cell dataset. Potential drugs were explored using the Drug Signatures Database (DSigDB). In vivo and in vitro experiments were performed to validate the pathogenetic mechanism of SCM and the therapeutic efficacy of candidate drugs.
RESULTS
Six hub mitochondria-related DEGs [MitoDEGs; translocase of inner mitochondrial membrane domain-containing 1 (TIMMDC1), mitochondrial ribosomal protein S31 (MRPS31), F-box only protein 7 (FBXO7), phosphatidylglycerophosphate synthase 1 (PGS1), LYR motif containing 7 (LYRM7), and mitochondrial chaperone BCS1 (BCS1L)] were identified. The diagnostic nomogram model based on the six hub genes demonstrated high reliability and validity in both the training and validation sets. The immunological microenvironment differed between SCM and control groups. The Spearman correlation analysis revealed that hub MitoDEGs were significantly associated with the infiltration of immune cells. Upregulated hub genes showed remarkably high expression in the naive/memory B cell, CD14 monocyte, and plasma cell subgroup, evidenced by the feature plot. The distribution of mitochondria/inflammation-related pathways varied across subgroups among control and SCM individuals. Metformin was predicted to be the most promising drug with the highest combined score. Its efficacy in restoring mitochondrial function and suppressing inflammatory responses has also been validated.
CONCLUSIONS
This study presents a comprehensive mitochondrial metabolism and immune infiltration landscape in SCM, providing a potential novel direction for the pathogenesis and medical intervention of SCM.
Topics: Humans; Reproducibility of Results; Mitochondria; Cardiomyopathies; DNA, Mitochondrial; Computational Biology; Inflammation; Sepsis; Mitochondrial Precursor Protein Import Complex Proteins; ATPases Associated with Diverse Cellular Activities; Electron Transport Complex III; Molecular Chaperones; Mitochondrial Proteins
PubMed: 38291374
DOI: 10.1186/s11658-024-00536-2 -
ELife Aug 2023Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The...
Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence these important physiological processes have yet to be explored. We present the 3.9 Å resolution cryo-EM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90-Cdc37, this work shows the remarkable plasticity of Cdc37 to interact with a broad array of clients with significant sequence variation. Furthermore, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of membrane receptor guanylyl cyclase-targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other membrane receptor guanylyl cyclase-related conditions.
Topics: Humans; Cell Cycle Proteins; Chaperonins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Binding; Receptors, Guanylate Cyclase-Coupled
PubMed: 37535399
DOI: 10.7554/eLife.86784 -
Nature Structural & Molecular Biology Dec 2023Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR)....
Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation.
Topics: Humans; Receptors, Glucocorticoid; Cryoelectron Microscopy; Tacrolimus Binding Proteins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Binding
PubMed: 37945740
DOI: 10.1038/s41594-023-01128-y -
Journal of Dairy Science Mar 2024Novel insights into the stability of milk and milk products during storage and processing result from describing caseins near neutral pH as hydrophilic, intrinsically...
Novel insights into the stability of milk and milk products during storage and processing result from describing caseins near neutral pH as hydrophilic, intrinsically disordered, proteins. Casein solubility is strongly influenced by pH and multivalent ion binding. Solubility is high at neutral pH or above but decreases as casein net charge approaches zero, allowing a condensed casein phase or gel to form then increases at lower pH. Of particular importance for casein micelle stability near neutral pH is the proportion of free caseins in the micelle (i.e., caseins not bound directly to nanoclusters of calcium phosphate). Free caseins are more soluble and better able to act as molecular chaperones (to prevent casein and whey protein aggregation) than bound caseins. Some free caseins are highly phosphorylated and can also act as mineral chaperones to inhibit the growth of calcium phosphate phases and prevent mineralized deposits from forming on membranes or heat exchangers. Thus, casein micelle stability is reduced when free caseins bind to amyloid fibrils, destabilized whey proteins or calcium phosphate. The multivalent-binding model of the casein micelle quantitatively describes these and other factors affecting the stability of milk and milk protein products during manufacture and storage.
PubMed: 38522835
DOI: 10.3168/jds.2024-24779 -
Annual Review of Virology Sep 2023Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing... (Review)
Review
Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing pandemics. One fundamental determinant of viral evolution is the interplay between viral protein biophysics and the host machineries that regulate protein folding and quality control. Most adaptive mutations in viruses are biophysically deleterious, resulting in a viral protein product with folding defects. In cells, protein folding is assisted by a dynamic system of chaperones and quality control processes known as the proteostasis network. Host proteostasis networks can determine the fates of viral proteins with biophysical defects, either by assisting with folding or by targeting them for degradation. In this review, we discuss and analyze new discoveries revealing that host proteostasis factors can profoundly shape the sequence space accessible to evolving viral proteins. We also discuss the many opportunities for research progress proffered by the proteostasis perspective on viral evolution and adaptation.
Topics: Proteostasis; Protein Folding; Molecular Chaperones; Viral Proteins; Viruses
PubMed: 37071930
DOI: 10.1146/annurev-virology-100220-112120 -
Hepatology (Baltimore, Md.) Sep 2023Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is...
BACKGROUND AND AIMS
Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage.
APPROACH AND RESULTS
C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation.
CONCLUSIONS
Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.
Topics: Animals; Mice; Mice, Inbred C57BL; Liver Diseases, Alcoholic; Liver; Ethanol; Mitochondria; Molecular Chaperones; Mitochondrial Proteins
PubMed: 36745935
DOI: 10.1097/HEP.0000000000000303 -
Cell Death & Disease Aug 2023Daxx functions as a histone chaperone for the histone H3 variant, H3.3, and is essential for embryonic development. Daxx interacts with Atrx to form a protein complex...
Daxx functions as a histone chaperone for the histone H3 variant, H3.3, and is essential for embryonic development. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres, and repeat loci. To advance our understanding of histone chaperone activity in vivo, we developed two Daxx mutant alleles in the mouse germline, which abolish the interactions between Daxx and Atrx (Daxx), and Daxx and H3.3 (Daxx). We found that the interaction between Daxx and Atrx is dispensable for viability; mice are born at the expected Mendelian ratio and are fertile. The loss of Daxx-Atrx interaction, however, does cause dysregulated expression of endogenous retroviruses. In contrast, the interaction between Daxx and H3.3, while not required for embryonic development, is essential for postnatal viability. Transcriptome analysis of embryonic tissues demonstrates that this interaction is important for silencing endogenous retroviruses and for maintaining proper immune cell composition. Overall, these results clearly demonstrate that Daxx has both Atrx-dependent and independent functions in vivo, advancing our understanding of this epigenetic regulatory complex.
Topics: Female; Pregnancy; Animals; Mice; Histone Chaperones; Embryonic Development; Alleles; Centromere; Molecular Chaperones; Co-Repressor Proteins
PubMed: 37633949
DOI: 10.1038/s41419-023-06089-0 -
International Journal of Molecular... Jul 2023Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), in which one of the trigger... (Review)
Review
Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), in which one of the trigger factors is represented by aberrant immune interactions between the intestinal epithelium and the intestinal microbiota. The involvement of heat shock proteins (HSPs) as etiological and pathogenetic factors is becoming of increasing interest. HSPs were found to be differentially expressed in the intestinal tissues and sera of patients with CD and UC. It has been shown that HSPs can play a dual role in the disease, depending on the stage of progression. They can support the inflammatory and fibrosis process, but they can also act as protective factors during disease progression or before the onset of one of the worst complications of IBD, colorectal cancer. Furthermore, HSPs are able to mediate the interaction between the intestinal microbiota and intestinal epithelial cells. In this work, we discuss the involvement of HSPs in IBD considering their genetic, epigenetic, immune and molecular roles, referring to the most recent works present in the literature. With our review, we want to shed light on the importance of further exploring the role of HSPs, or even better, the role of the molecular chaperone system (CS), in IBD: various molecules of the CS including HSPs may have diagnostic, prognostic and therapeutic potential, promoting the creation of new drugs that could overcome the side-effects of the therapies currently used.
Topics: Humans; Heat-Shock Proteins; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Intestines
PubMed: 37569505
DOI: 10.3390/ijms241512129