scholarly journals Deciphering Nuclear Mechanobiology in Laminopathy

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 231 ◽  
Author(s):  
Jungwon Hah ◽  
Dong-Hwee Kim
Keyword(s):  
Structural Integrity ◽  
Critical Role ◽  
Nuclear Lamina ◽  
Mechanical Stimuli ◽  
Cellular Mechanics ◽  
Know How ◽  
Disease Relevance ◽  
Biochemical Signals ◽  
Nuclear Response

Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy.

scholarly journals Vimentin filaments drive migratory persistence in polyploidal cancer cells

2020 ◽  
Vol 117 (43) ◽  
pp. 26756-26765
Author(s):  
Botai Xuan ◽  
Deepraj Ghosh ◽  
Joy Jiang ◽  
Rachelle Shao ◽  
Michelle R. Dawson
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Structural Integrity ◽  
Single Cell Analysis ◽  
Critical Role ◽  
Critical Function ◽  
Rna Knockdown ◽  
Interfering Rna ◽  
The Impact

Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.

scholarly journals Electric field mediated fibronectin-hydroxyapatite interaction: A molecular insight

2020 ◽  
Author(s):  
Subhadip Basu ◽  
Biswajit Gorai ◽  
Bikramjit Basu ◽  
Prabal K. Maiti
Keyword(s):  
Field Strength ◽  
Electric Field ◽  
Protein Adsorption ◽  
Structural Integrity ◽  
Critical Role ◽  
Field Stimulation ◽  
Electric Field Stimulation ◽  
Cell Material ◽  
Material Interaction

AbstractIn experimental research driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.), and to a relatively lesser extent, the biophysical stimulation (electric/magnetic) on the cell-material interaction has been extensively investigated. Considering the central importance of the protein adsorption on cell-material interaction, the role of physiochemical factors on the protein adsorption is also probed. Despite its significance, the quantitative analysis of many such aspects remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation towards modulation of cell functionality on implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on hydroxyapatite, HA (100) surface at 300K using all-atom MD simulation method. Fibronectin adsorption was found to be governed by the attractive electrostatic interaction, which changed with the electric field strength. Non-monotonous changes in structural integrity of fibronectin were recorded with the change in field strength and direction. This can be attributed to the spatial rearrangement of local charges and global structural changes of the protein. The dipole moment vectors of fibronectin, water and HA quantitatively exhibited similar pattern of orienting themselves parallel to the field direction, with field strength dependent increase in their magnitudes. No significant change has been recorded for radial distribution function of water surrounding fibronectin. Field dependent variation in the salt bridge nets and number of hydrogen bonds between fibronectin and hydroxyapatite were also examined. One of the important results in the context of the cell-material interaction is that the RGD sequence of FN was exposed to solvent side, when the field was applied along a direction outward perpendicular to HA (001) surface. Summarizing, the present study provides quantitative insights into the influence of electric field stimulation on biomolecular interactions involved in fibronectin adsorption on hydroxyapatite surface.

scholarly journals Lamin A/C Mechanotransduction in Laminopathies

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1306 ◽  
Author(s):  
Francesca Donnaloja ◽  
Federica Carnevali ◽  
Emanuela Jacchetti ◽  
Manuela Teresa Raimondi
Keyword(s):  
Chromatin Remodeling ◽  
Structural Integrity ◽  
Accelerated Aging ◽  
Nuclear Lamina ◽  
Cellular Processes ◽  
Skin Cells ◽  
Biological Responses ◽  
Associated Proteins ◽  
Nuclear Response ◽  
Cell Functionality

Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which are pathologies associated with mutations in lamins and lamin-associated proteins. These pathologies affect muscle, adipose, bone, nerve, and skin cells and range from muscular dystrophies to accelerated aging. Although the exact mechanisms governing laminopathies and gene expression are still not clear, a strong correlation has been found between cell functionality and nuclear behavior. New theories base on the direct effect of external force on the genome, which is indeed sensitive to the force transduced by the nuclear lamina. Nuclear lamina performs two essential functions in mechanotransduction pathway modulating the nuclear stiffness and governing the chromatin remodeling. Indeed, A-type lamin mutation and deregulation has been found to affect the nuclear response, altering several downstream cellular processes such as mitosis, chromatin organization, DNA replication-transcription, and nuclear structural integrity. In this review, we summarize the recent findings on the molecular composition and architecture of the nuclear lamina, its role in healthy cells and disease regulation. We focus on A-type lamins since this protein family is the most involved in mechanotransduction and laminopathies.

Nesprin-3: a versatile connector between the nucleus and the cytoskeleton

2011 ◽  
Vol 39 (6) ◽  
pp. 1719-1724 ◽  
Author(s):  
Mirjam Ketema ◽  
Arnoud Sonnenberg
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Actin Filaments ◽  
Structural Integrity ◽  
Nuclear Lamina ◽  
Cross Linking ◽  
Indirect Interaction ◽  
Direct Link ◽  
Nuclear Interior

The cytoskeleton is connected to the nuclear interior by LINC (linker of nucleoskeleton and cytoskeleton) complexes located in the nuclear envelope. These complexes consist of SUN proteins and nesprins present in the inner and outer nuclear membrane respectively. Whereas SUN proteins can bind the nuclear lamina, members of the nesprin protein family connect the nucleus to different components of the cytoskeleton. Nesprin-1 and -2 can establish a direct link with actin filaments, whereas nesprin-4 associates indirectly with microtubules through its interaction with kinesin-1. Nesprin-3 is the only family member known that can link the nuclear envelope to intermediate filaments. This indirect interaction is mediated by the binding of nesprin-3 to the cytoskeletal linker protein plectin. Furthermore, nesprin-3 can connect the nucleus to microtubules by its interactions with BPAG1 (bullous pemphigoid antigen 1) and MACF (microtubule–actin cross-linking factor). In contrast with the active roles that nesprin-1, -2 and -4 have in actin- and microtubule-dependent nuclear positioning, the role of nesprin-3 is likely to be more passive. We suggest that it helps to stabilize the anchorage of the nucleus within the cytoplasm and maintain the structural integrity and shape of the nucleus.

Investigation of the Role of Stress Fiber Contractility and Nucleus Geometry in the Response of Cells to Micropipette Aspiration

2012 ◽  
Author(s):  
Noel H. Reynolds ◽  
William Ronan ◽  
Enda P. Dowling ◽  
J. Patrick McGarry
Keyword(s):  
Actin Cytoskeleton ◽  
Critical Role ◽  
Stress Fiber ◽  
Micropipette Aspiration ◽  
Mechanical Stimuli ◽  
Cell Cytoplasm

Remodeling of the actin cytoskeleton plays a critical role in the response of cells to mechanical stimuli. Previous studies have investigated the response of cells to micropipette aspiration using passive visco-elastic models for the cell cytoplasm [1–3].

scholarly journals Regulation of Plasma Membrane Sterol Homeostasis by Nonvesicular Lipid Transport

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110424
Author(s):  
Dylan Hong Zheng Koh ◽  
Yasunori Saheki
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Structural Integrity ◽  
Critical Role ◽  
Lipid Transfer ◽  
Fusion Reactions ◽  
Lipid Transfer Proteins ◽  
Membrane Budding ◽  
Mode Of Transport

Sterol contributes to the structural integrity of cellular membranes and plays an important role in the regulation of cell signaling in eukaryotes. It is either produced in the endoplasmic reticulum or taken up from the extracellular environment. In most eukaryotic cells, however, the majority of sterol is enriched in the plasma membrane. Thus, the transport of sterol between the plasma membrane and other organelles, including the endoplasmic reticulum, is crucial for maintaining sterol homeostasis. While vesicular transport that relies on membrane budding and fusion reactions plays an important role in bulk sterol transport, this mode of transport is slow and non-selective. Growing evidence suggests a critical role of nonvesicular transport mediated by evolutionarily conserved families of lipid transfer proteins in more rapid and selective delivery of sterol. Some lipid transfer proteins act primarily at the sites of contacts formed between the endoplasmic reticulum and other organelles or the plasma membrane without membrane fusion. In this review, we describe the similarities and differences of sterol biosynthesis and uptake in mammals and yeast and discuss the role of their lipid transfer proteins in maintaining plasma membrane sterol homeostasis.

scholarly journals The Aftermath of Bronchoconstriction

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Michael J. O'Sullivan ◽  
Bo Lan
Keyword(s):  
Airway Inflammation ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Airway Remodeling ◽  
Critical Role ◽  
Mechanical Effect ◽  
Mechanical Stimuli ◽  
Underlying Mechanisms ◽  
New Evidence

Asthma is characterized by chronic airway inflammation, airway remodeling, and excessive constriction of the airway. Detailed investigation exploring inflammation and the role of immune cells has revealed a variety of possible mechanisms by which chronic inflammation drives asthma development. However, the underlying mechanisms of asthma pathogenesis still remain poorly understood. New evidence now suggests that mechanical stimuli that arise during bronchoconstriction may play a critical role in asthma development. In this article, we review the mechanical effect of bronchoconstriction and how these mechanical stresses contribute to airway remodeling independent of inflammation.

scholarly journals SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

2009 ◽  
Vol 20 (14) ◽  
pp. 3192-3199 ◽  
Author(s):  
Ryan J. Bourgo ◽  
Hasan Siddiqui ◽  
Sejal Fox ◽  
David Solomon ◽  
Courtney G. Sansam ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Structural Integrity ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Nucleosome Position ◽  
Proliferative Capacity ◽  
Central Importance ◽  
Evolutionarily Conserved ◽  
Chromatin Structural

Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity.

scholarly journals Potential Role of Drebrin A, an F-Actin Binding Protein, in Reactive Synaptic Plasticity after Pilocarpine-Induced Seizures: Functional Implications in Epilepsy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Lotfi Ferhat
Keyword(s):  
Structural Integrity ◽  
Synapse Formation ◽  
Specific Binding ◽  
Treatment Options ◽  
Critical Role ◽  
Synaptic Function ◽  
Actin Binding ◽  
Spine Density ◽  
Developmentally Regulated

Several neurological disorders characterized by cognitive deficits, including Alzheimer's disease, down syndrome, and epilepsy exhibit abnormal spine density and/or morphology. Actin-based cytoskeleton network dynamics is critical for the regulation of spine morphology and synaptic function. In this paper, I consider the functions of drebrin A in cell shaping, spine plasticity, and synaptic function. Developmentally regulated brain protein (drebrin A) is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines receiving excitatory inputs. Our recent findings point to a critical role of DA in dendritic spine structural integrity and stabilization, likely via regulation of actin cytoskeleton dynamics, and glutamatergic synaptic function that underlies the development of spontaneous recurrent seizures in pilocarpine-treated animals. Further research into this area may provide useful insights into the pathology of status epilepticus and epileptogenic mechanisms and ultimately may provide the basis for future treatment options.

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