Search Results (24)

In the silkworm, Bombyx mori (Lepidoptera: Bombycidae), the sex determination cascade is regulated by the cooperative actions of P-element somatic inhibitor (BmPSI) and Masculinizer (BmMasc), which control the sex-specific splicing of doublesex (Bmdsx). However, the functional interplay between these two critical factors remains poorly understood. In this study, we investigated the cooperative roles of BmPSI and BmMasc through transgenic overexpression and pull-down assays coupled with mass spectrometry. Co-overexpression of BmPSI and BmMasc resulted in female-specific lethality, whereas overexpression of either gene alone caused no lethality. Pull-down coupled with mass spectrometry identified 52 common interacting proteins of BmPSI and BmMasc, including Lethal(3)neo18, a mitochondrial respiratory chain Complex I core subunit, suggesting a potential link between sex determination and mitochondrial function. Transcriptome analysis of previously generated Bmdsx knockout mutants (Bmdsx^M, Bmdsx^F, and Bmdsx^C) revealed 703 commonly dysregulated genes, which were predominantly expressed in gonads and enriched in cytoskeletal and metabolic pathways. Notably, the oxidative phosphorylation pathway was enriched in both the Bmdsx mutant transcriptome and the BmPSI/BmMasc common interactome. Collectively, these findings indicate that BmPSI and BmMasc cooperate to regulate sex determination, and raise the possibility that synergistic disruption of mitochondrial function may underlie the female-specific lethality observed upon their co-overexpression. This study provides new insights into the molecular crosstalk between sex determination and mitochondrial metabolism in insects. Full article

Tumor cell migration relies on the integration of extracellular matrix (ECM) remodeling, cell surface signaling regulating cytoskeleton dynamics, and epithelial-to-mesenchymal transition (EMT). Clusterin (CLU), a secreted glycoprotein, is involved in extracellular proteostasis and is known to interact with members of the LDL receptor family, including low-density lipoprotein receptor-related protein 1 (LRP1). Beyond its canonical chaperone activity, CLU is involved in several biological processes, including cell survival, apoptosis, tissue remodeling, inflammation and cancer progression. On the other hand, the membrane type 1 matrix metalloproteinase (MT1-MMP), functionally linked to CD44 and LRP1, represents a key membrane-associated molecule that may control cell adhesion and receptor-mediated uptake of ECM ligands and proteases. In this article, we critically highlight a hypothetical model in which secreted CLU (sCLU) may function as the central player of a dynamic membrane-associated network integrating proteolysis, endocytosis, and intracellular signaling. Based on recent literature findings and STRING analyses, LRP1, MT1-MMP, CD44, and cell surface matrix components, such as proteoglycans (PGs) and integrins, are likely to be involved. By coordinating this membrane-associated molecular crosstalk, sCLU may integrate ECM remodeling with cytoskeletal dynamics and EMT-related programs related to invasive behavior. Overall, this framework highlights a potential mechanism through which sCLU may contribute to tumor cell plasticity and aggressiveness, suggesting new avenues for therapeutic intervention. Full article

Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues. Full article

Background: Titin (TTN), a giant structural and signaling protein of striated muscle, participates in intracellular signaling networks and cytoskeletal organization, potentially influencing cell activation, trafficking, and interactions with other tissues, including the heart. Methods: In this pilot study, 29 patients with acute myocarditis and 10 healthy individuals were prospectively enrolled. Peripheral blood was obtained on the first day of hospital admission, total RNA was isolated from peripheral blood mononuclear cells (PBMCs), and TTN mRNA expression was quantified. Results: TTN expression in PBMCs was significantly higher in patients with acute myocarditis compared with healthy controls (p = 0.015), corresponding to a 2.8-fold median increase. Moreover, TTN expression showed a strong positive correlation with global longitudinal strain impairment (Spearman’s r = 0.576, p < 0.001), a moderate positive correlation with peak hs-cTnI levels (r = 0.435, p = 0.021; and a moderate inverse correlation with baseline LVEF (r = −0.421, p = 0.025). Conclusions: These findings support a pathophysiological link between TTN-related pathways in peripheral immune cells and myocardial injury in acute myocarditis and raise the hypothesis that TTN expression in PBMCs may serve as a novel biomarker of disease severity and long-term ventricular remodeling. Further studies in larger cohorts are warranted to validate these results and to elucidate the mechanistic role of titin in immune–cardiac cross-talk. Full article

Tensins (TNS1–4) are pivotal molecular scaffolds bridging the actin cytoskeleton to integrin-based adhesions, orchestrating signal transduction and governing cellular processes in cancer. Structurally, the N-terminal actin-binding domain (ABD) in TNS1–3 enables cytoskeletal regulation and interactions with regulators like the Rho GAP DLC1, while ABD-deficient TNS4 functions as a focal adhesion signal amplifier. Functionally, TNS1–3 exhibit context-dependent duality as tumor promoters or suppressors, dictated by tissue-specific microenvironments and signaling crosstalk. In contrast, TNS4 acts predominantly as an oncoprotein across carcinomas by stabilizing epidermal growth factor receptor (EGFR), driving epithelial–mesenchymal transition and invasion, and sustaining proliferation. Clinically, tensin dysregulation correlates with metastasis and poor prognosis: TNS2 serves as a diagnostic biomarker for gastrointestinal stromal tumors, aberrant TNS1/TNS3 expression predicts metastasis risk, and TNS4 is recurrently embedded in multi-gene prognostic signatures. This review synthesizes their structural basis, regulatory mechanisms, and clinical relevance, highlighting context-dependent switches and TNS4’s therapeutic potential. Full article

Mechanical and contractile forces in the vascular wall regulate smooth muscle cell migration. We previously demonstrated the presence of C3 complement products in atherosclerotic lesions of human aortas and showed that that C3-derived fragments promote key cellular processes, such as actin cytoskeleton organization and cell migration, in lipid-loaded human vascular smooth muscle cells (hVSMCs). In the present study, we aimed to investigate gene expression profiles related to cytoskeletal remodeling and cell adhesion in migrating hVSMCs with a particular focus on modulatory effect of the C3 complement pathway on these processes. We analyzed gene expression in migrating and non-migrating hVSMCs using real-time PCR and in silico network analysis. Additionally, we investigated cytoskeletal remodeling through Western blotting and confocal microscopy. PCR profiling revealed 30 genes with significantly altered expression in migrating hVSMCs compared to non-migrating control cells. In silico analysis identified six of these genes—PXN, AKT1, RHOA, VCL, CTNNB1, and FN1—as being associated with cytoskeletal remodeling and focal adhesion, with PXN occupying a central position in the interaction network. PXN expression was reduced at both the transcript and protein levels and showed altered subcellular localization in migrating lipid-loaded hVSMCs. Protein–protein interaction analysis using STRING predicted an association between PXN and the integrin complex αMβ2 (comprising ITGAM (CD11b) and ITGB2 (CD18)), which functions as receptors for the iC3b complement fragment. Confocal imaging of cell adhesion structures revealed that lipid-loaded hVSMCs stimulated with iC3b displayed a more diffuse PXN distribution and significantly increased PXN–F-actin colocalization in active cytoplasmic regions compared to lipid-loaded control cells. PXN–F-actin colocalization increased from 1.26% to 19.68%. Subcellular fractionation further confirmed enhanced PXN enrichment in the membrane fraction, with no significant changes observed in the cytosolic or cytoskeletal compartments. In conclusion, iC3b-mediated molecular signaling in lipid-loaded hVSMCs alters PXN distribution and enhances cytoskeletal remodeling, revealing novel molecular interactions in vascular remodeling and the progression of atherosclerotic lesions. Full article

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

The aggregation of Tau protein into neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease (AD), is associated with cognitive decline. Recent studies have revealed that neuronal cytoskeletal instability drives early AD pathogenesis. The physiological interaction between tau and the microtubule (MT) is crucial for maintaining axonal transport and stability. However, aberrant post-translational modifications (PTMs) in the MT binding domain—such as phosphorylation, acetylation and ubiquitination—trigger tau dissociation, causing microtubule collapse, transport deficits, and synaptic dysfunction. MT dysregulation also affects actin/cofilin-mediated dendritic spine destabilization and causes the hyperplasia of the glial intermediate filament, which exacerbates neuroinflammation and synaptic toxicity. This review systematically explores the functions of neuronal cytoskeletons, deciphers the molecular crosstalk between tau pathology and cytoskeletal remodeling, and proposes multi-target therapeutic strategies to restore cytoskeletal homeostasis, thereby providing novel perspectives for precision interventions in AD Full article

The progression of colorectal cancer (CRC) is driven by dynamic interactions between tumor cells and their microenvironment, particularly the extracellular matrix (ECM). Ion channels, critical regulators of cellular signaling, have emerged as mediators of ECM remodeling and tumor aggressiveness. In this study, we integrate transcriptomic data from 185 CRC tumors and 157 adjacent normal tissues with network modeling to dissect the interplay between ion channels and the ECM. We identified 4036 differentially expressed genes (DEGs), including 188 ion channel-associated DEGs (IC-DEGs) enriched in ECM-related pathways, such as collagen assembly, matrix metalloproteinase regulation, and mechanotransduction. Structural equation modeling revealed an active CRC−ion channel module (CRC-IC) comprising 482 nodes and 422 edges, highlighting dysregulated interactions between ECM components (e.g., COL1A1, COL5A2, VCAN, LAMA4, LA-MA5, LAMC1), ion channels (e.g., TRPM5 and SLC16A1), and cytoskeletal regulators. Key nodes, including CHST11 and VCAN, were associated with ECM sulfation, tumor invasiveness, and immune evasion. Notably, survival was associated with MAPK1, SLC16A1, and ABCB4 in relation to patient prognosis. Our findings underscore the pivotal role of ion channels as co-factors in ECM dynamics in CRC, offering mechanistic insights into tumor-stroma crosstalk and identifying potential therapeutic targets to disrupt microenvironment-driven progression. Full article

Axon guidance, a fundamental process in neural circuit formation, is intricately regulated by Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) through dynamic cytoskeletal remodeling. FGF signaling, mediated by heparan sulfate proteoglycans or Klotho co-factors, activates key downstream pathways: PI3K-Akt, JAK-STAT, PLCγ, and RAS-MAPK. These pathways orchestrate actin filament dynamics, microtubule stability, and the organization of intermediate filaments. These pathways converge on Rho GTPases, cofilin, profilin, and tau to balance the cytoskeletal assembly−disassembly cycles, enabling growth cone navigation. Unresolved questions, such as the mechanisms underlying FGF-mediated growth cone steering, highlight critical future research directions. This review integrates structural, molecular, and functional insights into how FGF-FGFR interactions regulate axon pathfinding, emphasizing the crosstalk between signaling cascades and cytoskeletal plasticity. Elucidating these mechanisms not only advances our understanding of neural development but also opens therapeutic avenues for neuro-developmental disorders, nerve injury, and neurodegenerative diseases by targeting FGF-driven cytoskeletal dynamics. Full article

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons’ DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders. Full article

Viruses are obligate intracellular parasites that critically depend on their hosts to initiate infection, complete replication cycles, and generate new progeny virions. To achieve these goals, viruses have evolved numerous elegant strategies to subvert and utilize different cellular machinery. The cytoskeleton is often one of the first components to be hijacked as it provides a convenient transport system for viruses to enter the cell and reach the site of replication. The cytoskeleton is an intricate network involved in controlling the cell shape, cargo transport, signal transduction, and cell division. The host cytoskeleton has complex interactions with viruses during the viral life cycle, as well as cell-to-cell transmission once the life cycle is completed. Additionally, the host also develops unique, cytoskeleton-mediated antiviral innate immune responses. These processes are also involved in pathological damages, although the comprehensive mechanisms remain elusive. In this review, we briefly summarize the functions of some prominent viruses in inducing or hijacking cytoskeletal structures and the related antiviral responses in order to provide new insights into the crosstalk between the cytoskeleton and viruses, which may contribute to the design of novel antivirals targeting the cytoskeleton. Full article

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer, with over half of patients presenting with metastatic PDAC at diagnosis. Most patients receive conventional chemotherapy which invariably faces resistance, and a key facilitator in this is the PDAC stroma which acts as a functional mediator of disease progression through bilateral crosstalk between stromal cells and cancer cells. ‘Migrastatics’ are a new drug class which target cell migration pathway effector proteins to attenuate cancer cell invasion. Improvement in PDAC treatment strategy is well-overdue and migrastatics as adjuvant therapy is one avenue gaining traction. The p21-activated kinase (PAK) family is frequently overexpressed and/or amplified in PDAC where it regulates cytoskeletal actin contractility as well as transcription. Pre-clinical PAK inhibitors have shown reduced PDAC cell invasion in vitro, yet it is unknown how the PDAC stromal cells would respond to a PAK inhibitor and how this could consequently affect PDAC invasion. My PhD project investigates the Pancreatic stellate cell response to PAK inhibition. Full article

Hypoxia is an important risk for renal disease. The mitochondrial enzyme arginase-II (Arg-II) is expressed and/or induced by hypoxia in proximal tubular epithelial cells (PTECs) and in podocytes, leading to cellular damage. Because PTECs are vulnerable to hypoxia and located in proximity to podocytes, we examined the role of Arg-II in the crosstalk of PTECs under hypoxic conditions with podocytes. A human PTEC cell line (HK2) and a human podocyte cell line (AB8/13) were cultured. Arg-ii gene was ablated by CRISPR/Case9 in both cell types. HK2 cells were exposed to normoxia (21% O₂) or hypoxia (1% O₂) for 48 h. Conditioned medium (CM) was collected and transferred to the podocytes. Podocyte injuries were then analyzed. Hypoxic (not normoxic) HK2-CM caused cytoskeletal derangement, cell apoptosis, and increased Arg-II levels in differentiated podocytes. These effects were absent when arg-ii in HK2 was ablated. The detrimental effects of the hypoxic HK2-CM were prevented by TGF-β1 type-I receptor blocker SB431542. Indeed, TGF-β1 levels in hypoxic HK2-CM (but not arg-ii^−/−-HK2-CM) were increased. Furthermore, the detrimental effects of TGF-β1 on podocytes were prevented in arg-ii^−/−-podocytes. This study demonstrates crosstalk between PTECs and podocytes through the Arg-II-TGF-β1 cascade, which may contribute to hypoxia-induced podocyte damage. Full article

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed. Full article