-
BMC Musculoskeletal Disorders Dec 2023Current research on autophagy is mainly focused on intervertebral disc tissues and cells, while there is few on human peripheral blood sample. therefore, this study...
BACKGROUND
Current research on autophagy is mainly focused on intervertebral disc tissues and cells, while there is few on human peripheral blood sample. therefore, this study constructed a diagnostic model to identify autophagy-related markers of intervertebral disc degeneration (IVDD).
METHODS
GSE150408 and GSE124272 datasets were acquired from the Gene Expression Omnibus database, and differential expression analysis was performed. The IVDD-autophagy genes were obtained using Weighted Gene Coexpression Network Analysis, and a diagnostic model was constructed and validated, followed by Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA). Meanwhile, miRNA-gene and transcription factor-gene interaction networks were constructed. In addition, drug-gene interactions and target genes of methylprednisolone and glucosamine were analyzed.
RESULTS
A total of 1,776 differentially expressed genes were identified between IVDD and control samples, and the composition of the four immune cell types was significantly different between the IVDD and control samples. The Meturquoise and Mebrown modules were significantly related to immune cells, with significant differences between the control and IVDD samples. A diagnostic model was constructed using five key IVDD-autophagy genes. The area under the curve values of the model in the training and validation datasets were 0.907 and 0.984, respectively. The enrichment scores of the two pathways were significantly different between the IVDD and healthy groups. Eight pathways in the IVDD and healthy groups had significant differences. A total of 16 miRNAs and 3 transcription factors were predicted to be of great value. In total, 84 significantly related drugs were screened for five key IVDD-autophagy genes in the diagnostic model, and three common autophagy-related target genes of methylprednisolone and glucosamine were predicted.
CONCLUSION
This study constructs a reliable autophagy-related diagnostic model that is strongly related to the immune microenvironment of IVD. Autophagy-related genes, including PHF23, RAB24, STAT3, TOMM5, and DNAJB9, may participate in IVDD pathogenesis. In addition, methylprednisolone and glucosamine may exert therapeutic effects on IVDD by targeting CTSD, VEGFA, and BAX genes through apoptosis, as well as the sphingolipid and AGE-RAGE signaling pathways in diabetic complications.
Topics: Humans; Intervertebral Disc Degeneration; Intervertebral Disc; Transcription Factors; Autophagy; Methylprednisolone; Glucosamine; Membrane Proteins; Molecular Chaperones; HSP40 Heat-Shock Proteins; Homeodomain Proteins
PubMed: 38041088
DOI: 10.1186/s12891-023-06886-w -
International Journal of Molecular... Mar 2024A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties... (Review)
Review
A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties of dystonia can impact people of all ages, leading to severe impairment and a decreased standard of living. The discovery of genes causing variations of single or mixed dystonia has improved our understanding of the disease's etiology. Genetic dystonias are linked to several genes, including pathogenic variations of VPS16, TOR1A, THAP1, GNAL, and ANO3. Diagnosis of dystonia is primarily based on clinical symptoms, which can be challenging due to overlapping symptoms with other neurological conditions, such as Parkinson's disease. This review aims to summarize recent advances in the genetic origins and management of focal dystonia.
Topics: Humans; Dystonia; Dystonic Disorders; Movement; Parkinson Disease; Molecular Chaperones; DNA-Binding Proteins; Apoptosis Regulatory Proteins; Anoctamins
PubMed: 38612382
DOI: 10.3390/ijms25073571 -
Current Opinion in Microbiology Oct 2023Hsp90 is a conserved molecular chaperone that facilitates the folding and function of hundreds of client proteins, many of which serve as core hubs of signal... (Review)
Review
Hsp90 is a conserved molecular chaperone that facilitates the folding and function of hundreds of client proteins, many of which serve as core hubs of signal transduction networks. Hsp90 has a critical role in virulence of the opportunistic fungal pathogen Candida albicans, which exists as a natural commensal of the human microbiota and is a leading cause of invasive fungal infections, particularly in immunocompromised individuals. The ability of C. albicans to cause disease is tightly coupled to its capacity to undergo a morphogenetic transition between yeast and filamentous forms. Here, we describe the complex mechanisms by which Hsp90 regulates C. albicans morphogenesis and virulence, and explore the potential of targeting fungal Hsp90 as a therapeutic strategy to combat fungal infections.
Topics: Humans; Candida albicans; Fungal Proteins; Virulence; HSP90 Heat-Shock Proteins; Morphogenesis
PubMed: 37399670
DOI: 10.1016/j.mib.2023.102351 -
EMBO Molecular Medicine Nov 2023Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3...
Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients.
Topics: Animals; Humans; Mice; Carcinogenesis; Carcinoma, Squamous Cell; Endoplasmic Reticulum Chaperone BiP; Skin Neoplasms; Unfolded Protein Response
PubMed: 37807968
DOI: 10.15252/emmm.202317761 -
EMBO Reports Apr 2024Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe...
Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.
Topics: Animals; Humans; Male; Mice; Adaptor Proteins, Signal Transducing; Cytoskeletal Proteins; Dyneins; HSC70 Heat-Shock Proteins; Infertility, Male; Molecular Chaperones; Protein Folding; Semen; Sperm Head; Spermatogenesis; Spermatozoa; Teratozoospermia; Thiazoles
PubMed: 38454159
DOI: 10.1038/s44319-024-00112-x -
Experimental & Molecular Medicine Feb 2024H3.3, the most common replacement variant for histone H3, has emerged as an important player in chromatin dynamics for controlling gene expression and genome integrity.... (Review)
Review
H3.3, the most common replacement variant for histone H3, has emerged as an important player in chromatin dynamics for controlling gene expression and genome integrity. While replicative variants H3.1 and H3.2 are primarily incorporated into nucleosomes during DNA synthesis, H3.3 is under the control of H3.3-specific histone chaperones for spatiotemporal incorporation throughout the cell cycle. Over the years, there has been progress in understanding the mechanisms by which H3.3 affects domain structure and function. Furthermore, H3.3 distribution and relative abundance profoundly impact cellular identity and plasticity during normal development and pathogenesis. Recurrent mutations in H3.3 and its chaperones have been identified in neoplastic transformation and developmental disorders, providing new insights into chromatin biology and disease. Here, we review recent findings emphasizing how two distinct histone chaperones, HIRA and DAXX, take part in the spatial and temporal distribution of H3.3 in different chromatin domains and ultimately achieve dynamic control of chromatin organization and function. Elucidating the H3.3 deposition pathways from the available histone pool will open new avenues for understanding the mechanisms by which H3.3 epigenetically regulates gene expression and its impact on cellular integrity and pathogenesis.
Topics: Cell Cycle; Cell Division; Chromatin; Histone Chaperones; Histones; Humans; Molecular Chaperones; Co-Repressor Proteins; Transcription Factors; Cell Cycle Proteins
PubMed: 38297159
DOI: 10.1038/s12276-023-01145-3 -
Cell Death & Disease Oct 2023Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma in adults, exhibiting highly heterogenous clinical behavior and complex...
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma in adults, exhibiting highly heterogenous clinical behavior and complex molecular background. In addition to the genetic complexity, different DLBCL subsets exhibit phenotypic features independent of the genetic background. For example, a subset of DLBCLs is distinguished by increased oxidative phosphorylation and unique transcriptional features, including overexpression of certain mitochondrial genes and a molecular chaperone, heat shock protein HSP90α (termed "OxPhos" DLBCLs). In this study, we identified a feed-forward pathogenetic circuit linking HSP90α and SIRT1 in OxPhos DLBCLs. The expression of the inducible HSP90α isoform remains under SIRT1-mediated regulation. SIRT1 knockdown or chemical inhibition reduced HSP90α expression in a mechanism involving HSF1 transcription factor, whereas HSP90 inhibition reduced SIRT1 protein stability, indicating that HSP90 chaperones SIRT1. SIRT1-HSP90α interaction in DLBCL cells was confirmed by co-immunoprecipitation and proximity ligation assay (PLA). The number of SIRT1-HSP90α complexes in PLA was significantly higher in OxPhos- dependent than -independent cells. Importantly, SIRT1-HSP90α interactions in OxPhos DLBCLs markedly increased in mitosis, suggesting a specific role of the complex during this cell cycle phase. RNAi-mediated and chemical inhibition of SIRT1 and/or HSP90 significantly increased the number of cells with chromosome segregation errors (multipolar spindle formation, anaphase bridges and lagging chromosomes). Finally, chemical SIRT1 inhibitors induced dose-dependent cytotoxicity in OxPhos-dependent DLBCL cell lines and synergized with the HSP90 inhibitor. Taken together, our findings define a new OxPhos-DLBCL-specific pathogenetic loop involving SIRT1 and HSP90α that regulates chromosome dynamics during mitosis and may be exploited therapeutically.
Topics: Humans; Chromosome Segregation; HSP90 Heat-Shock Proteins; Lymphoma, Large B-Cell, Diffuse; Molecular Chaperones; Sirtuin 1
PubMed: 37816710
DOI: 10.1038/s41419-023-06186-0 -
Tremor and Other Hyperkinetic Movements... 2023Genetic factors have been implicated in the pathogenesis of blepharospasm (BSP), a dystonia characterized by excessive blinking and involuntary eyelid closure. Previous...
BACKGROUND
Genetic factors have been implicated in the pathogenesis of blepharospasm (BSP), a dystonia characterized by excessive blinking and involuntary eyelid closure. Previous research identified a co-segregating deleterious variant (GRCh38/hg38, NC_000009.12: g.127733410G>A, NM_001085347.3:c.568C>T, p. Arg190Cys) in three subjects with BSP and three carriers within a multi-generation pedigree. Other variants have been reported in patients with dystonia.
METHODS
Sanger sequencing was used to screen a cohort of 307 subjects with isolated BSP or BSP-plus dystonia affecting additional anatomical segments (BSP+). We also utilized computational tools to uniformly assess the deleteriousness and potential pathogenicity of previously reported variants.
RESULTS
There were no highly deleterious variants in the coding or contiguous splice site regions of within our cohort of 307 subjects.
DISCUSSION
Highly deleterious variants in are rare in patients with BSP/BSP+ phenotypes.
HIGHLIGHTS
Over 300 patients with BSP were screened for variants in , a (DYT1) homologue. No highly deleterious variants were identified in our cohort. The role of in BSP and other forms of dystonia remains indeterminant.
Topics: Humans; Blepharospasm; Dystonia; Dystonic Disorders; Molecular Chaperones; Pedigree
PubMed: 38076033
DOI: 10.5334/tohm.825 -
The Journal of Biological Chemistry Sep 2023Maintaining a functional proteome under different environmental conditions is challenging for every organism, in particular for unicellular organisms, such as bacteria.... (Review)
Review
Maintaining a functional proteome under different environmental conditions is challenging for every organism, in particular for unicellular organisms, such as bacteria. In order to cope with changing environments and stress conditions, bacteria depend on strictly coordinated proteostasis networks that control protein production, folding, trafficking, and degradation. Regulation of ribosome biogenesis and protein synthesis are cornerstones of this cellular adaptation in all domains of life, which is rationalized by the high energy demand of both processes and the increased resistance of translationally silent cells against internal or external poisons. Reduced protein synthesis ultimately also reduces the substrate load for protein transport systems, which are required for maintaining the periplasmic, inner, and outer membrane subproteomes. Consequences of impaired protein transport have been analyzed in several studies and generally induce a multifaceted response that includes the upregulation of chaperones and proteases and the simultaneous downregulation of protein synthesis. In contrast, generally less is known on how bacteria adjust the protein targeting and transport machineries to reduced protein synthesis, e.g., when cells encounter stress conditions or face nutrient deprivation. In the current review, which is mainly focused on studies using Escherichia coli as a model organism, we summarize basic concepts on how ribosome biogenesis and activity are regulated under stress conditions. In addition, we highlight some recent developments on how stress conditions directly impair protein targeting to the bacterial membrane. Finally, we describe mechanisms that allow bacteria to maintain the transport of stress-responsive proteins under conditions when the canonical protein targeting pathways are impaired.
Topics: Adaptation, Psychological; Escherichia coli; Escherichia coli Proteins; Heat-Shock Proteins; Protein Biosynthesis; Protein Transport
PubMed: 37586589
DOI: 10.1016/j.jbc.2023.105163 -
Oncoimmunology 2024Dendritic cells (DCs) play a key role in the induction of the adaptive immune response. They capture antigens in peripheral tissues and prime naïve T lymphocytes,...
Dendritic cells (DCs) play a key role in the induction of the adaptive immune response. They capture antigens in peripheral tissues and prime naïve T lymphocytes, triggering the adaptive immune response. In the course of inflammatory processes DCs face stressful conditions including hypoxia, low pH and high concentrations of reactive oxygen species (ROS), among others. How DCs survive under these adverse conditions remain poorly understood. Clusterin is a protein highly expressed by tumors and usually associated with bad prognosis. It promotes cancer cell survival by different mechanisms such as apoptosis inhibition and promotion of autophagy. Here, we show that, upon maturation, human monocyte-derived DCs (MoDCs) up-regulate clusterin expression. Clusterin protects MoDCs from ROS-mediated toxicity, enhancing DC survival and promoting their ability to induce T cell activation. In line with these results, we found that clusterin is expressed by a population of mature LAMP3+ DCs, called mregDCs, but not by immature DCs in human cancer. The expression of clusterin by intratumoral DCs was shown to be associated with a transcriptomic profile indicative of cellular response to stress. These results uncover an important role for clusterin in DC physiology.
Topics: Humans; Cell Death; Clusterin; Dendritic Cells; Neoplasms; Reactive Oxygen Species; T-Lymphocytes
PubMed: 38125724
DOI: 10.1080/2162402X.2023.2294564