Mobility of alpha-actinin along growing actin filaments might affect the cellular chirality

2021 ◽  
pp. 1-14
Author(s):  
Xi Li ◽  
Bin Chen
Keyword(s):  
Actin Filaments ◽  
Critical Role ◽  
Axial Direction ◽  
Biomechanical Properties ◽  
Model Analysis ◽  
Elastic Response ◽  
Cell Phenotype ◽  
Radial Fiber ◽  
Proper Functions

Abstract Chirality is a widespread feature existing in nature and can be critical in the proper functions of some organisms. In our previous work, a rotational clutch-filament model for a radial fiber was built to reveal the critical role of α-actinin in the cellular chiral swirling. Here we assume two mobility modes of α-actinin along actin filaments. In Mode A, where α-actinin concomitantly moves together with a growing filament, our model analysis suggests that cells cannot swirl clockwise; in Mode B, where α-actinin is fixed along the axial direction of the radial fiber instead, our model analysis suggests that both counter-clockwise and clockwise chiral swirling occur, in consistency with experiments. Thus, our studies suggest that how α-actinin moves along growing filaments within a radial fiber would strongly affect cellular swirling. In addition, the previous rotational clutch-model has been improved by considering the elastic response of a radial fiber to a torque and distributed biomechanical properties of varied cell phenotype.

scholarly journals DHA-phospholipids control membrane fusion and transcellular tunnel dynamics

2021 ◽  
Author(s):  
Meng-Chen Tsai ◽  
Lucile Fleuriot ◽  
Sébastien Janel ◽  
David Gonzalez-Rodriguez ◽  
Camille Morel ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Umbilical Vein ◽  
Critical Role ◽  
Biomechanical Properties ◽  
Cell Cortex ◽  
And Shifts ◽  
Umbilical Vein Endothelial Cells ◽  
The Impact ◽  
Cell Thickness

Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (PLs) in physiology. Here, we investigated the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) triggered by RhoA inhibition-associated cell spreading. Lipidomic analyses show that human umbilical vein endothelial cells (HUVECs) subjected to DHA-diet undergo a 6-fold enrichment in DHA-PLs at plasma membrane (PM) at the expense of monounsaturated OA-PLs. Consequently, DHA-PLs enrichment at the PM induces a reduction of cell thickness and shifts cellular membranes towards a permissive mode of membrane fusion for transcellular tunnel initiation. We provide evidence that a global homeostatic control of membrane tension and cell cortex rigidity minimizes overall changes of TEM area through a decrease of TEM size and lifetime. Conversely, low DHA-PL levels at the PM leads to the opening of unstable and wider TEMs. Together, this provides evidence that variations of DHA-PLs levels in membranes affect cell biomechanical properties.

scholarly journals The PCH family protein, Cdc15p, recruits two F-actin nucleation pathways to coordinate cytokinetic actin ring formation in Schizosaccharomyces pombe

2003 ◽  
Vol 162 (5) ◽  
pp. 851-862 ◽  
Author(s):  
Robert H. Carnahan ◽  
Kathleen L. Gould
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Actin Filaments ◽  
Critical Role ◽  
Ring Formation ◽  
Actin Nucleation ◽  
Actin Ring ◽  
Mutual Dependence ◽  
Family Protein

Cytokinetic actin ring (CAR) formation in Schizosaccharomyces pombe requires two independent actin nucleation pathways, one dependent on the Arp2/3 complex and another involving the formin Cdc12p. Here we investigate the role of the S. pombe Cdc15 homology family protein, Cdc15p, in CAR assembly and find that it interacts with proteins from both of these nucleation pathways. Cdc15p binds directly to the Arp2/3 complex activator Myo1p, which likely explains why actin patches and the Arp2/3 complex fail to be medially recruited during mitosis in cdc15 mutants. Cdc15p also binds directly to Cdc12p. Cdc15p and Cdc12p not only display mutual dependence for CAR localization, but also exist together in a ring-nucleating structure before CAR formation. The disruption of these interactions in cdc15 null cells is likely to be the reason for their complete lack of CARs. We propose a model in which Cdc15p plays a critical role in recruiting and coordinating the pathways essential for the assembly of medially located F-actin filaments and construction of the CAR.

scholarly journals Hypoxia induces an endometrial cancer stem-like cell phenotype via HIF-dependent demethylation of SOX2 mRNA

Oncogenesis ◽  
2020 ◽  
Vol 9 (9) ◽  
Author(s):  
Guofang Chen ◽  
Binya Liu ◽  
Shasha Yin ◽  
Shuangdi Li ◽  
Yu’e Guo ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
Cell Phenotype ◽  
Mrna Levels ◽  
Hypoxic Conditions ◽  
Inducing Factors ◽  
Tumour Initiation

Abstract Endometrial cancer stem cells (ECSCs) are stem-like cells endowed with self-renewal and differentiation abilities, and these cells are essential for cancer progression in endometrial cancer (EC). As hallmarks of the tumour microenvironment (TME), hypoxia and hypoxia-inducing factors (HIFs) give rise to the dysregulation of tumour stemness genes, such as SOX2. Against this backdrop, we investigated the regulatory mechanisms regulated by HIFs and SOX2 in ECSCs during EC development. Here, ECSCs isolated from EC cell lines and tissues were found to express stemness genes (CD133 and aldehyde dehydrogenase, ALDH1) following the induction of their ECSC expansion. Notably, m6A methylation of RNA and HIF-1α/2α-dependent AlkB homologue 5 (ALKBH5) participate in the regulation of HIFs and SOX2 in EC, as confirmed by the observations that mRNA levels of m6A demethylases and ALKBH5 significantly increase under hypoxic conditions in ECSCs. Moreover, hypoxia and high ALKBH5 levels restore the stem-like state of differentiated ECSCs and increase the ECSC-like phenotype, whereas the knockdown of HIFs or ALKBH5 significantly reduces their tumour initiation capacity. In addition, our findings validate the role of ALKBH5 in promoting SOX2 transcription via mRNA demethylation, thereby maintaining the stem-like state and tumorigenicity potential of ECSCs. In conclusion, these observations demonstrate a critical role for m6A methylation-mediated regulation of the HIF-ALKBH5-SOX2 axis during ECSC expansion in hypoxic TMEs.

scholarly journals Guanylate-Binding Protein 1 Inhibits Nuclear Delivery of Kaposi's Sarcoma-Associated Herpesvirus Virions by Disrupting Formation of Actin Filament

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Zhe Zou ◽  
Zhihua Meng ◽  
Chao Ma ◽  
Deguang Liang ◽  
Rui Sun ◽  
...  
Keyword(s):  
Immune System ◽  
Actin Filaments ◽  
Primary Infection ◽  
Rna Viruses ◽  
Critical Role ◽  
Host Cells ◽  
Host Immune System ◽  
Kshv Infection ◽  
Guanylate Binding Protein

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is a typical gammaherpesvirus that establishes persistent lifelong infection in host cells. In order to establish successful infection, KSHV has evolved numerous immune evasion strategies to bypass or hijack the host immune system. However, host cells still produce immune cytokines abundantly during primary KSHV infection. Whether the immune effectors produced are able to inhibit viral infection and how KSHV successfully conquers these immune effectors remain largely unknown. The guanylate-binding protein 1 (GBP1) gene is an interferon-stimulated gene and exerts antiviral functions on several RNA viruses; however, its function in DNA virus infection is less well understood. In this study, we found that KSHV infection increases both the transcriptional and protein levels of GBP1 at the early stage of primary infection by activating the NF-κB pathway. The overexpression of GBP1 significantly inhibited KSHV infection, while the knockdown of GBP1 promoted KSHV infection. The GTPase activity and dimerization of GBP1 were demonstrated to be responsible for its anti-KSHV activity. Furthermore, we found that GBP1 inhibited the nuclear delivery of KSHV virions by disrupting the formation of actin filaments. Finally, we demonstrated that replication and transcription activator (RTA) promotes the degradation of GBP1 through a proteasome pathway. Taken together, these results provide a new understanding of the antiviral mechanism of GBP1, which possesses potent anti-KSHV activity, and suggest the critical role of RTA in the evasion of the innate immune response during primary infection by KSHV. IMPORTANCE GBP1 can be induced by various cytokines and exerts antiviral activities against several RNA viruses. Our study demonstrated that GBP1 can exert anti-KSHV function by inhibiting the nuclear delivery of KSHV virions via the disruption of actin filaments. Moreover, we found that KSHV RTA can promote the degradation of GBP1 through a proteasome-mediated pathway. Taken together, our results elucidate a novel mechanism of GBP1 anti-KSHV activity and emphasize the critical role of RTA in KSHV evasion of the host immune system during primary infection.

Switching Cellular Swirling Upon One-Way Torsional Drive

2020 ◽  
Vol 87 (7) ◽  
Author(s):  
Xi Li ◽  
Bin Chen
Keyword(s):  
Actin Cytoskeleton ◽  
Model Prediction ◽  
Elastic Energy ◽  
Actin Filaments ◽  
Model Analysis ◽  
Radial Fiber ◽  
Experimental Findings ◽  
Molecular Components ◽  
Chiral System

Abstract In understanding how a radially symmetrical actin cytoskeleton spontaneously evolves into a chiral system, here we construct a torsional clutch-filament model for one radial fiber. The model analysis indicates that when actin filaments in growth tend to actively drive the radial fiber to only rotate counter-clockwise, certain amount of passive elastic energy also builds up within the radial fiber upon filament growth, the release of which tends to drive it to rotate clockwise. The competition between these two sources would eventually determine the cellular swirling direction, which can be counter-clockwise or clockwise. The model prediction is in consistency with recent experimental findings. This work provides understanding into how the cellular chirality can be modulated by varied molecular components associated with the cytoskeleton.

scholarly journals Stiffening of prostate cancer cells driven by actin filaments – microtubules crosstalk confers resistance to microtubule-targeting drugs

2020 ◽  
Author(s):  
Andrzej Kubiak ◽  
Matteo Chighizola ◽  
Carsten Schulte ◽  
Natalia Bryniarska ◽  
Julita Wesołowska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Actin Filaments ◽  
Biomechanical Properties ◽  
Living Cells ◽  
Prostate Cancer Cells ◽  
Force Microscopy ◽  
Atomic Force ◽  
Segregation Of Chromosomes

AbstractThe crucial role of microtubules in the mitotic-related segregation of chromosomes makes them an excellent target for anticancer microtubule targeting drugs (MTDs) such as vinflunine, colchicine, and docetaxel. MTDs affect mitosis by directly perturbing the structural organization of microtubules. By a direct assessment of the biomechanical properties of prostate cancer cells exposed to different MTDs using atomic force microscopy, we show that cell stiffening is a candidate mechanism through which cancer cells preserve the original phenotype in response to the application of MTDs. While changes in cellular rigidity are typically mainly attributed to remodeling of the actin filaments in the cytoskeleton, here we provide evidence that cell stiffening can be driven by a crosstalk between actin filaments and microtubules in drug-treated cells. Our findings improve the interpretation of biomechanical data obtained for living cells in studies of various physiological and pathological processes.

scholarly journals The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2788
Author(s):  
Robert Tempest ◽  
Sonia Guarnerio ◽  
Rawan Maani ◽  
Jamie Cooper ◽  
Nicholas Peake
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Transglutaminase 2 ◽  
Biomechanical Properties ◽  
Tumour Microenvironment ◽  
Cell Phenotype ◽  
Tissue Remodelling ◽  
Direct Role ◽  
Mesenchymal Transition ◽  
Cellular Processes

Transglutaminase-2 (TG2) is the most highly and ubiquitously expressed member of the transglutaminase enzyme family and is primarily involved in protein cross-linking. TG2 has been implicated in the development and progression of numerous cancers, with a direct role in multiple cellular processes and pathways linked to apoptosis, chemoresistance, epithelial-mesenchymal transition, and stem cell phenotype. The tumour microenvironment (TME) is critical in the formation, progression, and eventual metastasis of cancer, and increasing evidence points to a role for TG2 in matrix remodelling, modulation of biomechanical properties, cell adhesion, motility, and invasion. There is growing interest in targeting the TME therapeutically in response to advances in the understanding of its critical role in disease progression, and a number of approaches targeting biophysical properties and biomechanical signalling are beginning to show clinical promise. In this review we aim to highlight the wide array of processes in which TG2 influences the TME, focussing on its potential role in the dynamic tissue remodelling and biomechanical events increasingly linked to invasive and aggressive behaviour. Drug development efforts have yielded a range of TG2 inhibitors, and ongoing clinical trials may inform strategies for targeting the biomolecular and biomechanical function of TG2 in the TME.

scholarly journals Role of NRF2 in Lung Cancer

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1879
Author(s):  
Miriam Sánchez-Ortega ◽  
Ana Clara Carrera ◽  
Antonio Garrido
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Critical Role ◽  
Defense Responses ◽  
Cell Phenotype ◽  
Cell Protection ◽  
Cell Defense

The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.

scholarly journals Critical role of acute hypoxemia on the cognitive impairment after severe COVID-19 pneumonia: a multivariate causality model analysis

2022 ◽  
Author(s):  
Miguel García-Grimshaw ◽  
Amanda Chirino-Pérez ◽  
Fernando Daniel Flores-Silva ◽  
Sergio Iván Valdés-Ferrer ◽  
María de los Ángeles Vargas-Martínez ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Critical Role ◽  
Model Analysis ◽  
Causality Model

Quantitative Model-Based Image Analysis of NuMa Distribution Links Nuclear Organization with Cell Phenotype

2001 ◽  
Vol 7 (S2) ◽  
pp. 578-579
Author(s):  
David W. Knowles ◽  
Sophie A. Lelièvre ◽  
Carlos Ortiz de Solόrzano ◽  
Stephen J. Lockett ◽  
Mina J. Bissell ◽  
...  
Keyword(s):  
Image Analysis ◽  
Mammary Epithelial Cells ◽  
Nuclear Organization ◽  
Critical Role ◽  
Quantitative Model ◽  
Mammary Epithelial ◽  
Cell Phenotype ◽  
Proliferating Cells ◽  
Mitotic Apparatus ◽  
Model Based

The extracellular matrix (ECM) plays a critical role in directing cell behaviour and morphogenesis by regulating gene expression and nuclear organization. Using non-malignant (S1) human mammary epithelial cells (HMECs), it was previously shown that ECM-induced morphogenesis is accompanied by the redistribution of nuclear mitotic apparatus (NuMA) protein from a diffuse pattern in proliferating cells, to a multi-focal pattern as HMECs growth arrested and completed morphogenesis . A process taking 10 to 14 days.To further investigate the link between NuMA distribution and the growth stage of HMECs, we have investigated the distribution of NuMA in non-malignant S1 cells and their malignant, T4, counter-part using a novel model-based image analysis technique. This technique, based on a multi-scale Gaussian blur analysis (Figure 1), quantifies the size of punctate features in an image. Cells were cultured in the presence and absence of a reconstituted basement membrane (rBM) and imaged in 3D using confocal microscopy, for fluorescently labeled monoclonal antibodies to NuMA (fαNuMA) and fluorescently labeled total DNA.

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