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Proceedings of the National Academy of... Sep 2023Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential...
Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential for the plasticity and remodeling that underlie behavioral adaptations. Importantly, the mechanisms of actin assembly have been well-defined-including that it is driven by actin's polymerization into filaments (F-actin) and then often bundling by crosslinking proteins into stable higher-order structures. In contrast, it remains less clear how these stable bundled F-actin structures are rapidly disassembled. We now uncover mechanisms that rapidly and extensively disassemble bundled F-actin. Using biochemical, structural, and imaging assays with purified proteins, we show that F-actin bundled with one of the most prominent crosslinkers, fascin, is extensively disassembled by Mical, the F-actin disassembly enzyme. Furthermore, the product of this Mical effect, Mical-oxidized actin, is poorly bundled by fascin, thereby further amplifying Mical's disassembly effects on bundled F-actin. Moreover, another critical F-actin regulator, cofilin, also affects fascin-bundled filaments, but we find herein that it synergizes with Mical to dramatically amplify its disassembly of bundled F-actin compared to the sum of their individual effects. Genetic and high-resolution cellular assays reveal that Mical also counteracts crosslinking proteins/bundled F-actin in vivo to control cellular extension, axon guidance, and Semaphorin/Plexin cell-cell repulsion. Yet, our results also support the idea that fascin-bundling serves to dampen Mical's F-actin disassembly in vitro and in vivo-and that physiologically relevant cellular remodeling requires a fine-tuned interplay between the factors that build bundled F-actin networks and those that disassemble them.
Topics: Actins; Actin Depolymerizing Factors; Actin Cytoskeleton; Cytoskeleton; Axon Guidance
PubMed: 37725655
DOI: 10.1073/pnas.2309955120 -
Current Protein & Peptide Science 2023Thymosin β4 (Tβ4) is the β-thymosin (Tβs) with the highest expression level in human cells; it makes up roughly 70-80% of all Tβs in the human body. Combining the... (Review)
Review
Thymosin β4 (Tβ4) is the β-thymosin (Tβs) with the highest expression level in human cells; it makes up roughly 70-80% of all Tβs in the human body. Combining the mechanism and activity studies of Tβ4 in recent years, we provide an overview of the subtle molecular mechanism, pharmacological action, and clinical applications of Tβ4. As a G-actin isolator, Tβ4 inhibits the polymerization of G-actin by binding to the matching site of G-actin in a 1:1 ratio through conformational and spatial effects. Tβ4 can control the threshold concentration of G-actin in the cytoplasm, influence the balance of depolymerization and polymerization of F-actin (also called Tread Milling of F-actin), and subsequently affect cell's various physiological activities, especially motility, development and differentiation. Based on this, Tβ4 is known to have a wide range of effects, including regulation of inflammation and tumor metastasis, promotion of angiogenesis, wound healing, regeneration of hair follicles, promotion of the development of the nervous system, and improving bone formation and tooth growth. Tβ4 therefore has extensive medicinal applications in many fields, and serves to preserve the kidney, liver, heart, brain, intestine, and other organs, as well as hair loss, skin trauma, cornea repairing, and other conditions. In this review, we focus on the mechanism of action and clinical application of Tβ4 for its main biological functions.
Topics: Humans; Actins; Actin Cytoskeleton; Thymosin; Wound Healing
PubMed: 36464872
DOI: 10.2174/1389203724666221201093500 -
Molecular Biology of the Cell Nov 2023Many eukaryotic cells, including animal cells and unicellular amoebae, use dynamic-actin networks to crawl across solid surfaces. Recent discoveries of actin-dependent... (Review)
Review
Many eukaryotic cells, including animal cells and unicellular amoebae, use dynamic-actin networks to crawl across solid surfaces. Recent discoveries of actin-dependent crawling in additional lineages have sparked interest in understanding how and when this type of motility evolved. Tracing the evolution of cell crawling requires understanding the molecular mechanisms underlying motility. Here we outline what is known about the diversity and evolution of the molecular mechanisms that drive cell motility, with a focus on actin-dependent crawling. Classic studies and recent work have revealed a surprising number of distinct mechanical modes of actin-dependent crawling used by different cell types and species to navigate different environments. The overlap in actin network regulators driving multiple types of actin-dependent crawling, along with cortical-actin networks that support the plasma membrane in these cells, suggest that actin motility and cortical actin networks might have a common evolutionary origin. The rapid development of additional evolutionarily diverse model systems, advanced imaging technologies, and CRISPR-based genetic tools, is opening the door to testing these and other new ideas about the evolution of actin-dependent cell crawling.
Topics: Animals; Actins; Cell Movement; Cell Membrane
PubMed: 37906436
DOI: 10.1091/mbc.E22-08-0358 -
Handbook of Experimental Pharmacology 2017Seven decades of research have revealed much about actin structure, assembly, regulatory proteins, and cellular functions. However, some key information is still... (Review)
Review
Seven decades of research have revealed much about actin structure, assembly, regulatory proteins, and cellular functions. However, some key information is still missing, so we do not understand the mechanisms of most processes that depend on actin. This chapter summarizes our current knowledge and explains some examples of work that will be required to fill these gaps and arrive at a mechanistic understanding of actin biology.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Animals; Cell Movement; Humans; Polymerization
PubMed: 27873086
DOI: 10.1007/164_2016_44 -
Trends in Cell Biology Jul 2017Actin filaments and associated proteins undergo wave-like movement in various cell types. Recent studies with cutting-edge analyses, including live-cell imaging,... (Review)
Review
Actin filaments and associated proteins undergo wave-like movement in various cell types. Recent studies with cutting-edge analyses, including live-cell imaging, biophysical monitoring and manipulation, and mathematical modeling, have highlighted roles of 'actin waves' in cellular protrusion, polarization, and migration. The prevailing models to explain the wave-like dynamics of actin filaments involve an activator-inhibitor mechanism. In addition, axonal actin waves migrate by means of directional assembly and disassembly of membrane-anchored actin filaments, and thus represent a new type of machinery that translocates their component molecules to the cell edge. Here, we review recent advances in our understanding of the generation, mobility, and functions of actin waves, and discuss how actin waves may self-organize into the molecular machinery underlying cell morphogenesis.
Topics: Actins; Cell Movement; Cell Polarity; Humans
PubMed: 28283221
DOI: 10.1016/j.tcb.2017.02.003 -
ELife Nov 2023The MRTF-SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various...
The MRTF-SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various cell types. However, the specific contribution of MRTF-SRF in hair cells remains unknown. In this study, we showed that hair cell-specific deletion of or , but not a, leads to similar defects in the development of stereocilia dimensions and the maintenance of cuticular plate integrity. We used fluorescence-activated cell sorting-based hair cell RNA-Seq analysis to investigate the mechanistic underpinnings of the changes observed in and mutants, respectively. Interestingly, the transcriptome analysis revealed distinct profiles of genes regulated by and , suggesting different transcriptional regulation mechanisms of actin cytoskeleton activities mediated by and . Exogenous delivery of calponin 2 using Adeno-associated virus transduction in mutants partially rescued the impairments of stereocilia dimensions and the F-actin intensity of cuticular plate, suggesting the involvement of , as an downstream target, in regulating the hair bundle morphology and cuticular plate actin cytoskeleton organization. Our study uncovers, for the first time, the unexpected differential transcriptional regulation of actin cytoskeleton mediated by and in hair cells, and also demonstrates the critical role of SRF-CNN2 in modulating actin dynamics of the stereocilia and cuticular plate, providing new insights into the molecular mechanism underlying hair cell development and maintenance.
Topics: Hair Cells, Auditory; Actin Cytoskeleton; Stereocilia; Actins; Gene Expression Regulation
PubMed: 37982489
DOI: 10.7554/eLife.90155 -
Handbook of Experimental Pharmacology 2017Actin is the central building block of the actin cytoskeleton, a highly regulated filamentous network enabling dynamic processes of cells and simultaneously providing... (Review)
Review
Actin is the central building block of the actin cytoskeleton, a highly regulated filamentous network enabling dynamic processes of cells and simultaneously providing structure. Mammals have six actin isoforms that are very conserved and thus share common functions. Tissue-specific expression in part underlies their differential roles, but actin isoforms also coexist in various cell types and tissues, suggesting specific functions and preferential interaction partners. Gene deletion models, antibody-based staining patterns, gene silencing effects, and the occurrence of isoform-specific mutations in certain diseases have provided clues for specificity on the subcellular level and its consequences on the organism level. Yet, the differential actin isoform functions are still far from understood in detail. Biochemical studies on the different isoforms in pure form are just emerging, and investigations in cells have to deal with a complex and regulated system, including compensatory actin isoform expression.
Topics: Actins; Animals; Humans; Mutation; Protein Isoforms
PubMed: 27757757
DOI: 10.1007/164_2016_43 -
Biochemistry. Biokhimiia Jun 2019Actin plays an important role in cellular adhesion, muscle and non-muscle contractility, migration, polarization, mitosis, and meiosis. Investigation of specific... (Review)
Review
Actin plays an important role in cellular adhesion, muscle and non-muscle contractility, migration, polarization, mitosis, and meiosis. Investigation of specific mechanisms underlying these processes is essential not only for fundamental research but also for clinical applications, since modulations of actin isoforms are directly or indirectly correlate with severe pathologies. In this review we summarize the isoform-specific functions of actin associated with adhesion structures, motility and division of normal and tumor cells; alterations of the expression and structural organization of actin isoforms in normal and tumor cells. Selective regulation of cytoplasmic β- or γ-actin expression determines functional diversity between isoforms: β-actin plays the predominant role in contraction and intercellular adhesion, and γ-actin is responsible for the cellular plasticity and motility. Similar data were obtained in different epithelial and mesenchymal neoplastic cell cultures, as well as in immunomorphological comparison of normal human tissues with tumor analogues. Reorganization of the actin cytoskeleton and cell-cell contacts is essential for proliferation control and acquisition of invasiveness in epithelial tumors.
Topics: Actins; Animals; Cell Adhesion; Cell Movement; Cell Transformation, Neoplastic; Cytoplasm; Cytosol; Humans; Mammals; Protein Isoforms; Structure-Activity Relationship
PubMed: 31238858
DOI: 10.1134/S0006297919060014 -
Current Topics in Microbiology and... 2017Actin is one of the most abundant proteins in any eukaryotic cell and an indispensable component of the cytoskeleton. In mammalian organisms, six highly conserved actin... (Review)
Review
Actin is one of the most abundant proteins in any eukaryotic cell and an indispensable component of the cytoskeleton. In mammalian organisms, six highly conserved actin isoforms can be distinguished, which differ by only a few amino acids. In non-muscle cells, actin polymerizes into actin filaments that form actin structures essential for cell shape stabilization, and participates in a number of motile activities like intracellular vesicle transport, cytokinesis, and also cell locomotion. Here, we describe the structure of monomeric and polymeric actin, the polymerization kinetics, and its regulation by actin-binding proteins. Probably due to its conserved nature and abundance, actin and its regulating factors have emerged as prefered targets of bacterial toxins and effectors, which subvert the host actin cytoskeleton to serve bacterial needs.
Topics: Actins; Animals; Bacteria; Bacterial Infections; Bacterial Toxins; Humans; Microfilament Proteins; Protein Binding
PubMed: 27848038
DOI: 10.1007/82_2016_45 -
Communications Biology Sep 2023Actin, an important component of eukaryotic cell cytoskeleton, regulates cell shape and transport. The morphology and biochemical properties of actin filaments are...
Actin, an important component of eukaryotic cell cytoskeleton, regulates cell shape and transport. The morphology and biochemical properties of actin filaments are determined by their structure and protein-protein contacts. Crowded environments can organize filaments into bundles, but less is known about how they affect F-actin structure. This study used 2D IR spectroscopy and spectral calculations to examine how crowding and bundling impact the secondary structure and local environments in filaments and weakly or strongly bundled networks. The results reveal that bundling induces changes in actin's secondary structure, leading to a decrease in β-sheet and an increase in loop conformations. Strongly bundled networks exhibit a decrease in backbone solvent exposure, with less perturbed α-helices and nearly "locked" β-sheets. Similarly, the loops become less hydrated but maintain a dynamic environment. These findings highlight the role of loop structure in actin network morphology and stability under morphology control by PEG.
Topics: Actins; Actin Cytoskeleton; Protein Structure, Secondary; Cytoskeleton; Cell Shape
PubMed: 37660224
DOI: 10.1038/s42003-023-05274-3