Scaffold, mechanics and functions of nuclear lamins

FEBS Letters, Год журнала: 2023, Номер 597(22), С. 2791 - 2805

Опубликована: Окт. 10, 2023

Nuclear lamins are type-V intermediate filaments that involved in many nuclear processes. In mammals, A- and B-type assemble into separate physical meshwork underneath the inner membrane, lamina, with some residual fraction localized within nucleoplasm. Lamins major part of nucleoskeleton, providing mechanical strength flexibility to protect genome allow deformability, while also contributing gene regulation via interactions chromatin. While evolutionary ancestors all filament family proteins, their ultimate filamentous assembly is markedly different from cytoplasmic counterparts. Interestingly, hundreds genetic mutations lamina proteins have been causally linked a broad range human pathologies, termed laminopathies. These include muscular, neurological metabolic disorders, as well premature aging diseases. Recent technological advances contributed resolving structure corresponding organization. this review, we revisit multiscale lamin organization discuss its implications on mechanics chromatin lamina-associated domains.

Язык: Английский

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Actin contraction controls nuclear blebbing and rupture independent of actin confinement

Molecular Biology of the Cell, Год журнала: 2023, Номер 35(2)

Опубликована: Дек. 13, 2023

The nucleus is a mechanically stable compartment of the cell that contains genome and performs many essential functions. Nuclear mechanical components chromatin lamins maintain nuclear shape, compartmentalization, function by resisting antagonistic actin contraction confinement. Studies have yet to compare perturbations side-by-side as well modulated while holding confinement constant. To accomplish this, we used localization signal green fluorescent protein measure shape rupture in live cells with lamin perturbations. We then maintaining measured height. Wild type, decompaction, B1 null present bleb-based deformations ruptures dependent on independent Actin inhibition Y27632 decreased blebbing activation CN03 increased frequency. Lamin A/C results overall abnormal also reliant contraction, but similar blebs wild type. Increased DNA damage caused or which can be relieved rescues decreases levels all Thus, drives blebbing, ruptures, changes

Язык: Английский

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Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases

Pharmacology & Therapeutics, Год журнала: 2023, Номер 250, С. 108528 - 108528

Опубликована: Сен. 13, 2023

Язык: Английский

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Abnormal open states patterns in the ATXN2 DNA sequence depends on the CAG repeats length

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 276, С. 133849 - 133849

Опубликована: Июль 14, 2024

Язык: Английский

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Implications of Cellular Mechanical Memory in Bioengineering

ACS Biomaterials Science & Engineering, Год журнала: 2023, Номер 9(11), С. 5985 - 5998

Опубликована: Окт. 5, 2023

The ability to maintain and differentiate cells in vitro is critical many advances the field of bioengineering. However, on traditional, stiff (E ≈ GPa) culture substrates, are subjected sustained mechanical stress that can lead phenotypic changes. Such changes may remain even after transferring another scaffold or engrafting them vivo bias outcomes biological investigation clinical treatment. This persistence─or memory─was initially observed for myofibroblast activation pulmonary fibroblasts culturing 100 kPa) substrates. Aspects memory have now been described contexts. In this Review, we discuss stiffness-induced effectors memory: structural cytoskeleton activity transcription factors epigenetic modifiers. We then focus how impacts cell expansion tissue regeneration bioengineering applications relying prolonged 2D plastic culture, such as stem therapies disease models. propose alternatives traditional substrates be used mitigate erase improve efficiency downstream cell-based applications.

Язык: Английский

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Structural anisotropy results in mechano-directional transport of proteins across nuclear pores

Nature Physics, Год журнала: 2024, Номер 20(7), С. 1180 - 1193

Опубликована: Май 13, 2024

The nuclear pore complex regulates nucleocytoplasmic transport by means of a tightly synchronized suite biochemical reactions. physicochemical properties the translocating cargos are emerging as master regulators their shuttling dynamics. As well being affected molecular weight and surface-exposed amino acids, kinetics translocation protein also depend on nanomechanical properties, yet mechanisms underpinning mechanoselectivity unclear. Here we show that proteins with locally soft regions in vicinity nuclear-localization sequence exhibit higher nuclear-import rates, such is specifically impaired upon knocking down nucleoporin 153, key complex. This allows us to design short, easy-to-express chemically inert unstructured peptide tag accelerates rate stiff cargos. We U2OS osteosarcoma cells expressing peptide-tagged myocardin-related transcription factor import this mechanosensitive nucleus at rates display faster motility. Locally lower free-energy barrier might offer control mechanism for mechanotransduction.

Язык: Английский

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A survey of physical methods for studying nuclear mechanics and mechanobiology

APL Bioengineering, Год журнала: 2021, Номер 5(4)

Опубликована: Ноя. 18, 2021

It is increasingly appreciated that the cell nucleus not only a home for DNA but also complex material resists physical deformations and dynamically responds to external mechanical cues. The molecules confer properties nuclei certainly contribute laminopathies possibly cellular mechanotransduction processes in cancer such as metastasis. Studying nuclear mechanics downstream biochemical consequences or their modulation requires suite of assays applying, measuring, visualizing forces across diverse length, time, force scales. Here, we review current methods mechanobiology, placing specific emphasis on each unique advantages limitations. Furthermore, explore important considerations selecting new methodology are demonstrated by recent examples from literature. We conclude providing an outlook development judicious use techniques continued exploration into role mechanobiology.

Язык: Английский

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Chromatin condensation regulates endothelial cell adaptation to shear stress

Molecular Biology of the Cell, Год журнала: 2022, Номер 33(11)

Опубликована: Сен. 7, 2022

Vascular endothelial cells (ECs) have been shown to be mechanoresponsive the forces of blood flow, including fluid shear stress (FSS), frictional force on vessel wall. Recent reports that FSS induces epigenetic changes in chromatin. Epigenetic changes, such as methylation and acetylation histones, not only affect gene expression but also chromatin condensation, which can alter nuclear stiffness. Thus, we hypothesized condensation may an important component for how ECs adapt FSS. Using both vitro vivo models EC adaptation FSS, observed increase histone a decrease adapted flow compared with static. small molecule drugs, well vascular growth factor, change show decreasing enables more quickly align whereas increasing inhibited alignment. Additionally, data prevent or DNA damage, measured by phosphorylation γH2AX. Taken together, these results indicate potentially extension stiffness, is aspect

Язык: Английский

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Comparative membrane proteomics reveals diverse cell regulators concentrated at the nuclear envelope

Life Science Alliance, Год журнала: 2023, Номер 6(9), С. e202301998 - e202301998

Опубликована: Июль 11, 2023

The nuclear envelope (NE) is a subdomain of the ER with prominent roles in organization, which are largely mediated by its distinctive protein composition. We developed methods to reveal low-abundance transmembrane (TM) proteins concentrated at NE relative peripheral ER. Using label-free proteomics that compared isolated NEs cytoplasmic membranes, we first identified apparent enrichment. In subsequent authentication, ectopically expressed candidates were analyzed immunofluorescence microscopy quantify their targeting cultured cells. Ten from validation set found associate preferentially NE, including oxidoreductases, enzymes for lipid biosynthesis, and regulators cell growth survival. determined one validated candidates, palmitoyltransferase Zdhhc6, modifies oxidoreductase Tmx4 thereby modulates levels. This provides functional rationale concentration Zdhhc6. Overall, our methodology has revealed group previously unrecognized additional candidates. Future analysis these can potentially unveil new mechanistic pathways associated NE.

Язык: Английский

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The LINC complex in blood vessels: from physiology to pathological implications in arterioles

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Abstract The LINC (linker of nucleoskeleton and cytoskeleton) complex is a critical component the cellular architecture that bridges cytoskeleton mediates mechanotransduction to from nucleus. Though it plays important roles in all blood vessels, arterioles this pivotal role maintaining endothelial cell integrity, regulating vascular tone, forming new microvessels modulating responses mechanical biochemical stimuli. It also smooth muscle cells fibroblasts, where possibly contractile secretory phenotypic transformation during atherosclerosis ageing, fibroblasts' migration inflammatory adventitia. Physiologically, contributes stability arteriolar structure, adaptations changes flow injury repair mechanisms. Pathologically, dysregulation or mutations components can lead compromised function, remodelling exacerbation cardiovascular diseases such as (arteriolosclerosis). This review summarizes our current understanding arterioles, highlighting its most physiological functions, exploring implications for pathology emphasizing some functional characteristics cells. By elucidating complex's health disease, we aim provide insights could improve future therapeutic strategies targeting complex‐related disorders. image

Язык: Английский

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