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1.
Cell Commun Signal ; 22(1): 208, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566066

RESUMO

This review presents a comprehensive exploration of the pivotal role played by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, with a particular focus on Nesprin proteins, in cellular mechanics and the pathogenesis of muscular diseases. Distinguishing itself from prior works, the analysis delves deeply into the intricate interplay of the LINC complex, emphasizing its indispensable contribution to maintaining cellular structural integrity, especially in mechanically sensitive tissues such as cardiac and striated muscles. Additionally, the significant association between mutations in Nesprin proteins and the onset of Dilated Cardiomyopathy (DCM) and Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their pivotal role in disease pathogenesis. Through a comprehensive examination of DCM and EDMD cases, the review elucidates the disruptions in the LINC complex, nuclear morphology alterations, and muscular developmental disorders, thus emphasizing the essential function of an intact LINC complex in preserving muscle physiological functions. Moreover, the review provides novel insights into the implications of Nesprin mutations for cellular dynamics in the pathogenesis of muscular diseases, particularly in maintaining cardiac structural and functional integrity. Furthermore, advanced therapeutic strategies, including rectifying Nesprin gene mutations, controlling Nesprin protein expression, enhancing LINC complex functionality, and augmenting cardiac muscle cell function are proposed. By shedding light on the intricate molecular mechanisms underlying nuclear-cytoskeletal interactions, the review lays the groundwork for future research and therapeutic interventions aimed at addressing genetic muscle disorders.


Assuntos
Doenças Musculares , Distrofia Muscular de Emery-Dreifuss , Humanos , Membrana Nuclear/metabolismo , Membrana Nuclear/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças Musculares/metabolismo , Citoesqueleto/metabolismo , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/metabolismo , Distrofia Muscular de Emery-Dreifuss/patologia
2.
PLoS One ; 19(4): e0300539, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38574058

RESUMO

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNA-seq. This signature includes genes likely to attenuate DLK signaling while simultaneously inducing actin regulating genes. We identify alterations to the cytoskeleton including actin-based morphological changes to the axon. These results are consistent with the model that cytoskeletal disruption in the neuron induces a DLK-dependent homeostatic mechanism, which we term the Cytoskeletal Stress Response (CSR) pathway.


Assuntos
Actinas , Axônios , Axônios/metabolismo , Nocodazol/farmacologia , Actinas/metabolismo , Zíper de Leucina , Regeneração Nervosa/fisiologia , Citoesqueleto/metabolismo , Homeostase , MAP Quinase Quinase Quinases/genética
3.
J Cell Sci ; 137(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38563209

RESUMO

Actin is well known for its cytoskeletal functions, where it helps to control and maintain cell shape and architecture, as well as regulating cell migration and intracellular cargo transport, among others. However, actin is also prevalent in the nucleus, where genome-regulating roles have been described, including it being part of chromatin-remodeling complexes. More recently, with the help of advances in microscopy techniques and specialized imaging probes, direct visualization of nuclear actin filament dynamics has helped elucidate new roles for nuclear actin, such as in cell cycle regulation, DNA replication and repair, chromatin organization and transcriptional condensate formation. In this Cell Science at a Glance article, we summarize the known signaling events driving the dynamic assembly of actin into filaments of various structures within the nuclear compartment for essential genome functions. Additionally, we highlight the physiological role of nuclear F-actin in meiosis and early embryonic development.


Assuntos
Actinas , Núcleo Celular , Actinas/metabolismo , Núcleo Celular/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto/metabolismo , Ciclo Celular
4.
Sci Adv ; 10(11): eadj1512, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38478607

RESUMO

Endoplasmic reticulum (ER)-plasma membrane (PM) tethering is crucial for the non-vesicular lipid transport between the ER membrane and the PM. However, the PM-associated ER can impede the PM binding of cytoskeletons and other organelles. It is poorly understood how the competition between the ER and cytoskeletons/organelles on the PM is resolved. Here, we show that, upon septin collar assembly, ER-PM tethering proteins are excluded from the yeast bud sites, and the PM-associated ER is locally detached from the PM. Our results suggest that PM flows by polarized exocytosis extrude PM proteins, including ER-PM tethering proteins, from the bud sites. When the reorganization of the ER-PM tethering was inhibited by exocytosis repression, septin localization was restricted to the PM sites poor in ER-PM tethering proteins. This study proposes machinery reconciling ER-septin competition on the PM, providing mechanistic insights into the spatial organization of PM-associated organelles and cytoskeletons.


Assuntos
Retículo Endoplasmático , Septinas , Septinas/metabolismo , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Saccharomyces cerevisiae/metabolismo , Citoesqueleto/metabolismo
5.
Cells ; 13(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474334

RESUMO

The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction-cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed.


Assuntos
Citoesqueleto , Junções Intercelulares , Animais , Citoesqueleto/metabolismo , Junções Intercelulares/metabolismo , Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Chaperonas Moleculares/metabolismo , Mamíferos/metabolismo
6.
Nat Commun ; 15(1): 2477, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509115

RESUMO

How a developing organ robustly coordinates the cellular mechanics and growth to reach a final size and shape remains poorly understood. Through iterations between experiments and model simulations that include a mechanistic description of interkinetic nuclear migration, we show that the local curvature, height, and nuclear positioning of cells in the Drosophila wing imaginal disc are defined by the concurrent patterning of actomyosin contractility, cell-ECM adhesion, ECM stiffness, and interfacial membrane tension. We show that increasing cell proliferation via different growth-promoting pathways results in two distinct phenotypes. Triggering proliferation through insulin signaling increases basal curvature, but an increase in growth through Dpp signaling and Myc causes tissue flattening. These distinct phenotypic outcomes arise from differences in how each growth pathway regulates the cellular cytoskeleton, including contractility and cell-ECM adhesion. The coupled regulation of proliferation and cytoskeletal regulators is a general strategy to meet the multiple context-dependent criteria defining tissue morphogenesis.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Morfogênese/fisiologia , Citoesqueleto/metabolismo , Transdução de Sinais/fisiologia , Asas de Animais , Drosophila melanogaster/metabolismo
7.
ACS Nano ; 18(12): 8919-8933, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38489155

RESUMO

The orchestrated assembly of actin and actin-binding proteins into cytoskeletal structures coordinates cell morphology changes during migration, cytokinesis, and adaptation to external stimuli. The accurate and unbiased visualization of the diverse actin assemblies within cells is an ongoing challenge. We describe here the identification and use of designed ankyrin repeat proteins (DARPins) as synthetic actin binders. Actin-binding DARPins were identified through ribosome display and validated biochemically. When introduced or expressed inside living cells, fluorescently labeled DARPins accumulated at actin filaments, validated through phalloidin colocalization on fixed cells. Nevertheless, different DARPins displayed different actin labeling patterns: some DARPins labeled efficiently dynamic structures, such as filopodia, lamellipodia, and blebs, while others accumulated primarily in stress fibers. This differential intracellular distribution correlated with DARPin-actin binding kinetics, as measured by fluorescence recovery after photobleaching experiments. Moreover, the rapid arrest of actin dynamics induced by pharmacological treatment led to the fast relocalization of DARPins. Our data support the hypothesis that the localization of actin probes depends on the inherent dynamic movement of the actin cytoskeleton. Compared to the widely used LifeAct probe, one DARPin exhibited enhanced signal-to-background ratio while retaining a similar ability to label stress fibers. In summary, we propose DARPins as promising actin-binding proteins for labeling or manipulation in living cells.


Assuntos
Actinas , Proteínas de Repetição de Anquirina Projetadas , Actinas/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto de Actina/metabolismo , Proteínas dos Microfilamentos/metabolismo
8.
Nucleus ; 15(1): 2330947, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38533923

RESUMO

Cellular behavior is continuously influenced by mechanical forces. These forces span the cytoskeleton and reach the nucleus, where they trigger mechanotransduction pathways that regulate downstream biochemical events. Therefore, the nucleus has emerged as a regulator of cellular response to mechanical stimuli. Cell cycle progression is regulated by cyclin-CDK complexes. Recent studies demonstrated these biochemical pathways are influenced by mechanical signals, highlighting the interdependence of cellular mechanics and cell cycle regulation. In particular, the transition from G2 to mitosis (G2-M) shows significant changes in nuclear structure and organization, ranging from nuclear pore complex (NPC) and nuclear lamina disassembly to chromosome condensation. The remodeling of these mechanically active nuclear components indicates that mitotic entry is particularly sensitive to forces. Here, we address how mechanical forces crosstalk with the nucleus to determine the timing and efficiency of the G2-M transition. Finally, we discuss how the deregulation of nuclear mechanics has consequences for mitosis.


Assuntos
Núcleo Celular , Mecanotransdução Celular , Núcleo Celular/metabolismo , Mitose , Citoesqueleto/metabolismo , Biofísica
9.
Int J Mol Sci ; 25(6)2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38542408

RESUMO

Septins play a key regulatory role in cell division, cytokinesis, and cell polar growth of the rice blast fungus (Magnaporthe oryzae). We found that the organization of the septin ring, which is essential for appressorium-mediated infection in M. oryzae, requires long-chain fatty acids (LCFAs), which act as mediators of septin organization at membrane interfaces. However, it is unclear how septin ring formation and LCFAs regulate the pathogenicity of the rice blast fungus. In this study, a novel protein was named MoLfa1 because of its role in LCFAs utilization. MoLfa1 affects the utilization of LCFAs, lipid metabolism, and the formation of the septin ring by binding with phosphatidylinositol phosphates (PIPs), thereby participating in the construction of penetration pegs of M. oryzae. In addition, MoLfa1 is localized in the endoplasmic reticulum (ER) and interacts with the ER-related protein MoMip11 to affect the phosphorylation level of Mps1. (Mps1 is the core protein in the MPS1-MAPK pathway.) In conclusion, MoLfa1 affects conidia morphology, appressorium formation, lipid metabolism, LCFAs utilization, septin ring formation, and the Mps1-MAPK pathway of M. oryzae, influencing pathogenicity.


Assuntos
Ascomicetos , Magnaporthe , Oryza , Septinas/metabolismo , Proteínas Fúngicas/metabolismo , Magnaporthe/fisiologia , Citoesqueleto/metabolismo , Oryza/metabolismo , Doenças das Plantas/microbiologia , Esporos Fúngicos/metabolismo , Regulação Fúngica da Expressão Gênica
10.
PLoS Biol ; 22(3): e3002551, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38466773

RESUMO

Mammals have 6 highly conserved actin isoforms with nonredundant biological functions. The molecular basis of isoform specificity, however, remains elusive due to a lack of tools. Here, we describe the development of IntAct, an internal tagging strategy to study actin isoforms in fixed and living cells. We identified a residue pair in ß-actin that permits tag integration and used knock-in cell lines to demonstrate that IntAct ß-actin expression and filament incorporation is indistinguishable from wild type. Furthermore, IntAct ß-actin remains associated with common actin-binding proteins (ABPs) and can be targeted in living cells. We demonstrate the usability of IntAct for actin isoform investigations by showing that actin isoform-specific distribution is maintained in human cells. Lastly, we observed a variant-dependent incorporation of tagged actin variants into yeast actin patches, cables, and cytokinetic rings demonstrating cross species applicability. Together, our data indicate that IntAct is a versatile tool to study actin isoform localization, dynamics, and molecular interactions.


Assuntos
Actinas , Proteínas dos Microfilamentos , Animais , Humanos , Actinas/genética , Actinas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Citoesqueleto de Actina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Citoesqueleto/metabolismo , Saccharomyces cerevisiae/metabolismo , Mamíferos/metabolismo
11.
Cell Commun Signal ; 22(1): 184, 2024 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-38493137

RESUMO

BACKGROUND: Injury to contractile organs such as the heart, vasculature, urinary bladder and gut can stimulate a pathological response that results in loss of normal contractility. PDGF and TGFß are among the most well studied initiators of the injury response and have been shown to induce aberrant contraction in mechanically active cells of hollow organs including smooth muscle cells (SMC) and fibroblasts. However, the mechanisms driving contractile alterations downstream of PDGF and TGFß in SMC and fibroblasts are incompletely understood, limiting therapeutic interventions. METHODS: To identify potential molecular targets, we have leveraged the analysis of publicly available data, comparing transcriptomic changes in mechanically active cells stimulated with PDGF and TGFß. Additional Analysis of publicly available data sets were performed on SMC and fibroblasts treated in the presence or absence of the MYC inhibitor JQ1. Validation of in silico findings were performed with qPCR, immunoblots, and collagen gel contraction assays measure the effect of JQ1 on cytoskeleton associated genes, proteins and contractility in mechanically active cells. Likelihood ratio test and FDR adjusted p-values were used to determine significant differentially expressed genes. Student ttest were used to calculate statistical significance of qPCR and contractility analyses. RESULTS: Comparing PDGF and TGFß stimulated SMC and fibroblasts identified a shared molecular profile regulated by MYC and members of the AP-1 transcription factor complex. Additional in silico analysis revealed a unique set of cytoskeleton-associated genes that were sensitive to MYC inhibition with JQ1. In vitro validation demonstrated JQ1 was also able to attenuate TGFß and PDGF induced changes to the cytoskeleton and contraction of smooth muscle cells and fibroblasts in vitro. CONCLUSIONS: These findings identify MYC as a key driver of aberrant cytoskeletal and contractile changes in fibroblasts and SMC, and suggest that JQ1 could be used to restore normal contractile function in hollow organs.


Assuntos
Proteínas Nucleares , Fatores de Transcrição , Humanos , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Citoesqueleto/metabolismo , Miócitos de Músculo Liso , Fator de Crescimento Transformador beta/metabolismo , Células Cultivadas
12.
Nat Commun ; 15(1): 2547, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514695

RESUMO

Focal adhesions (FAs) connect inner workings of cell to the extracellular matrix to control cell adhesion, migration and mechanosensing. Previous studies demonstrated that FAs contain three vertical layers, which connect extracellular matrix to the cytoskeleton. By using super-resolution iPALM microscopy, we identify two additional nanoscale layers within FAs, specified by actin filaments bound to tropomyosin isoforms Tpm1.6 and Tpm3.2. The Tpm1.6-actin filaments, beneath the previously identified α-actinin cross-linked actin filaments, appear critical for adhesion maturation and controlled cell motility, whereas the adjacent Tpm3.2-actin filament layer beneath seems to facilitate adhesion disassembly. Mechanistically, Tpm3.2 stabilizes ACF-7/MACF1 and KANK-family proteins at adhesions, and hence targets microtubule plus-ends to FAs to catalyse their disassembly. Tpm3.2 depletion leads to disorganized microtubule network, abnormally stable FAs, and defects in tail retraction during migration. Thus, FAs are composed of distinct actin filament layers, and each may have specific roles in coupling adhesions to the cytoskeleton, or in controlling adhesion dynamics.


Assuntos
Actinas , Adesões Focais , Actinas/metabolismo , Adesões Focais/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto/metabolismo , Isoformas de Proteínas/metabolismo
13.
Int J Mol Sci ; 25(6)2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38542155

RESUMO

Peptidylarginine deiminases (PADs or PADIs) catalyze the conversion of positively charged arginine to neutral citrulline, which alters target protein structure and function. Our previous work established that gonadotropin-releasing hormone agonist (GnRHa) stimulates PAD2-catalyzed histone citrullination to epigenetically regulate gonadotropin gene expression in the gonadotrope-derived LßT2 cell line. However, PADs are also found in the cytoplasm. Given this, we used mass spectrometry (MS) to identify additional non-histone proteins that are citrullinated following GnRHa stimulation and characterized the temporal dynamics of this modification. Our results show that actin and tubulin are citrullinated, which led us to hypothesize that GnRHa might induce their citrullination to modulate cytoskeletal dynamics and architecture. The data show that 10 nM GnRHa induces the citrullination of ß-actin, with elevated levels occurring at 10 min. The level of ß-actin citrullination is reduced in the presence of the pan-PAD inhibitor biphenyl-benzimidazole-Cl-amidine (BB-ClA), which also prevents GnRHa-induced actin reorganization in dispersed murine gonadotrope cells. GnRHa induces the citrullination of ß-tubulin, with elevated levels occurring at 30 min, and this response is attenuated in the presence of PAD inhibition. To examine the functional consequence of ß-tubulin citrullination, we utilized fluorescently tagged end binding protein 1 (EB1-GFP) to track the growing plus end of microtubules (MT) in real time in transfected LßT2 cells. Time-lapse confocal microscopy of EB1-GFP reveals that the MT average lifetime increases following 30 min of GnRHa treatment, but this increase is attenuated by PAD inhibition. Taken together, our data suggest that GnRHa-induced citrullination alters actin reorganization and MT lifetime in gonadotrope cells.


Assuntos
Actinas , Citrulinação , Camundongos , Animais , Actinas/metabolismo , Tubulina (Proteína)/metabolismo , Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Citrulina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hidrolases/metabolismo
14.
J Am Chem Soc ; 146(13): 8895-8903, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38511265

RESUMO

Actin is one of the most abundant proteins in eukaryotic cells and is a key component of the cytoskeleton. A range of small molecules has emerged that interfere with actin dynamics by either binding to polymeric F-actin or monomeric G-actin to stabilize or destabilize filaments or prevent their formation and growth, respectively. Among these, the latrunculins, which bind to G-actin and affect polymerization, are widely used as tools to investigate actin-dependent cellular processes. Here, we report a photoswitchable version of latrunculin, termed opto-latrunculin (OptoLat), which binds to G-actin in a light-dependent fashion and affords optical control over actin polymerization. OptoLat can be activated with 390-490 nm pulsed light and rapidly relaxes to its inactive form in the dark. Light activated OptoLat induced depolymerization of F-actin networks in oligodendrocytes and budding yeast, as shown by fluorescence microscopy. Subcellular control of actin dynamics in human cancer cell lines was demonstrated via live cell imaging. Light-activated OptoLat also reduced microglia surveillance in organotypic mouse brain slices while ramification was not affected. Incubation in the dark did not alter the structural and functional integrity of the microglia. Together, our data demonstrate that OptoLat is a useful tool for the elucidation of G-actin dependent dynamic processes in cells and tissues.


Assuntos
Citoesqueleto de Actina , Actinas , Animais , Camundongos , Humanos , Actinas/química , Citoesqueleto de Actina/metabolismo , Citoesqueleto/metabolismo , Linhagem Celular , Microtúbulos/metabolismo
15.
J Cell Biol ; 223(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38551496

RESUMO

Phytopathogens cause plant diseases that threaten food security. Unlike mammals, plants lack an adaptive immune system and rely on their innate immune system to recognize and respond to pathogens. Plant response to a pathogen attack requires precise coordination of intracellular traffic and signaling. Spatial and/or temporal defects in coordinating signals and cargo can lead to detrimental effects on cell development. The role of intracellular traffic comes into a critical focus when the cell sustains biotic stress. In this review, we discuss the current understanding of the post-immune activation logistics of plant defense. Specifically, we focus on packaging and shipping of defense-related cargo, rerouting of intracellular traffic, the players enabling defense-related traffic, and pathogen-mediated subversion of these pathways. We highlight the roles of the cytoskeleton, cytoskeleton-organelle bridging proteins, and secretory vesicles in maintaining pathways of exocytic defense, acting as sentinels during pathogen attack, and the necessary elements for building the cell wall as a barrier to pathogens. We also identify points of convergence between mammalian and plant trafficking pathways during defense and highlight plant unique responses to illustrate evolutionary adaptations that plants have undergone to resist biotic stress.


Assuntos
Imunidade Inata , Plantas , Animais , Citoesqueleto/metabolismo , Mamíferos , Organelas/metabolismo , Plantas/imunologia , Plantas/metabolismo , Transdução de Sinais
16.
Cell Rep ; 43(3): 113791, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38428420

RESUMO

The "ribbon," a structural arrangement in which Golgi stacks connect to each other, is considered to be restricted to vertebrate cells. Although ribbon disruption is linked to various human pathologies, its functional role in cellular processes remains unclear. In this study, we investigate the evolutionary origin of the Golgi ribbon. We observe a ribbon-like architecture in the cells of several metazoan taxa suggesting its early emergence in animal evolution predating the appearance of vertebrates. Supported by AlphaFold2 modeling, we propose that the evolution of Golgi reassembly and stacking protein (GRASP) binding by golgin tethers may have driven the joining of Golgi stacks resulting in the ribbon-like configuration. Additionally, we find that Golgi ribbon assembly is a shared developmental feature of deuterostomes, implying a role in embryogenesis. Overall, our study points to the functional significance of the Golgi ribbon beyond vertebrates and underscores the need for further investigations to unravel its elusive biological roles.


Assuntos
Complexo de Golgi , Proteínas de Membrana , Animais , Humanos , Proteínas de Membrana/metabolismo , Complexo de Golgi/metabolismo , Citoesqueleto/metabolismo , Células HeLa , Vertebrados
17.
Anal Cell Pathol (Amst) ; 2024: 6681911, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487684

RESUMO

Phospholipase D (PLD) is an enzyme that consists of six isoforms (PLD1-PLD6) and has been discovered in different organisms including bacteria, viruses, plants, and mammals. PLD is involved in regulating a wide range of nerve cells' physiological processes, such as cytoskeleton modulation, proliferation/growth, vesicle trafficking, morphogenesis, and development. Simultaneously, PLD, which also plays an essential role in the pathogenesis of neurodegenerative and neuroimmune diseases. In this review, family members, characterizations, structure, functions and related signaling pathways, and therapeutic values of PLD was summarized, then five representative diseases including Alzheimer disease (AD), Parkinson's disease (PD), etc. were selected as examples to tell the involvement of PLD in these neurological diseases. Notably, recent advances in the development of tools for studying PLD therapy envisaged novel therapeutic interventions. Furthermore, the limitations of PLD based therapy were also analyzed and discussed. The content of this review provided a thorough and reasonable basis for further studies to exploit the potential of PLD in the treatment of neurodegenerative and neuroimmune diseases.


Assuntos
Fosfolipase D , Animais , Fosfolipase D/química , Fosfolipase D/metabolismo , Isoformas de Proteínas/metabolismo , Citoesqueleto/metabolismo , Transdução de Sinais , Mamíferos/metabolismo
18.
Methods Mol Biol ; 2761: 267-276, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427243

RESUMO

Cytoskeletal and microtubule atrophy are major hallmarks of Alzheimer's disease (AD). A method to investigate endogenous proteins that can interact/stabilize the cytoskeleton (under pathological cues) is rare. Here, we describe how receptor tyrosine kinase-like orphan receptor 1 (ROR1), a receptor tyrosine kinase (RTK), can act as a neuroprotective molecule by promoting neurite outgrowth, stabilizing cytoskeletal components, and altering the dynamics of actin assembly in a cell culture model of AD.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Actinas/metabolismo , Citoesqueleto/metabolismo , Técnicas de Cultura de Células , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética
19.
Methods Mol Biol ; 2761: 257-266, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427242

RESUMO

Cytoskeletal dysregulation forms an important aspect of many neurodegenerative diseases such as Alzheimer's disease. Cytoskeletal functions require the dynamic activity of the cytoskeletal proteins-actin, tubulin, and the associated proteins. One of such important phenomena is that of actin remodeling, which helps the cell to migrate, navigate, and interact with extracellular materials. Podosomes are complex actin-rich cytoskeletal structures, abundant in proteins that interact and degrade the extracellular matrix, enabling cells to displace and migrate. The formation of podosomes requires extensive actin networks and remodeling. Here we present a novel immunofluorescence-based approach to study actin remodeling in neurons through the medium of podosomes.


Assuntos
Actinas , Podossomos , Actinas/metabolismo , Podossomos/metabolismo , Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/metabolismo , Matriz Extracelular/metabolismo , Citoesqueleto de Actina/metabolismo
20.
Nat Commun ; 15(1): 1840, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418447

RESUMO

The cytoskeletal protein actin plays a critical role in the pathogenicity of the intracellular parasite, Toxoplasma gondii, mediating invasion and egress, cargo transport, and organelle inheritance. Advances in live cell imaging have revealed extensive filamentous actin networks in the Apicomplexan parasite, but there are conflicting data regarding the biochemical and biophysical properties of Toxoplasma actin. Here, we imaged the in vitro assembly of individual Toxoplasma actin filaments in real time, showing that native, unstabilized filaments grow tens of microns in length. Unlike skeletal muscle actin, Toxoplasma filaments intrinsically undergo rapid treadmilling due to a high critical concentration, fast monomer dissociation, and rapid nucleotide exchange. Cryo-EM structures of jasplakinolide-stabilized and native (i.e. unstabilized) filaments show an architecture like skeletal actin, with differences in assembly contacts in the D-loop that explain the dynamic nature of the filament, likely a conserved feature of Apicomplexan actin. This work demonstrates that evolutionary changes at assembly interfaces can tune the dynamic properties of actin filaments without disrupting their conserved structure.


Assuntos
Parasitos , Toxoplasma , Animais , Actinas/metabolismo , Toxoplasma/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto/metabolismo , Parasitos/metabolismo
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