European journal of cell biology最新文献

{"title":"The mechanical mechanism of angiotensin II induced activation of hepatic stellate cells promoting portal hypertension","authors":"Yiheng Zhang ,&nbsp;Mulan Xing ,&nbsp;Fansheng Meng ,&nbsp;Ling Zhu ,&nbsp;Qingchuan Huang ,&nbsp;Tianle Ma ,&nbsp;Huihua Fang ,&nbsp;Xujing Gu ,&nbsp;Suzhou Huang ,&nbsp;Xinyu Wu ,&nbsp;Gaohong Lv ,&nbsp;Jun Guo ,&nbsp;Li Wu ,&nbsp;Xin Liu ,&nbsp;Zhipeng Chen","doi":"10.1016/j.ejcb.2024.151427","DOIUrl":"10.1016/j.ejcb.2024.151427","url":null,"abstract":"<div><p>In the development of chronic liver disease, the hepatic stellate cell (HSC) plays a pivotal role in increasing intrahepatic vascular resistance (IHVR) and inducing portal hypertension (PH) in cirrhosis. Our research demonstrated that HSC contraction, prompted by angiotensin II (Ang II), significantly contributed to the elevation of type I collagen (COL1A1) expression. This increase was intimately associated with enhanced cell tension and YAP nuclear translocation, mediated through α-smooth muscle actin (α-SMA) expression, microfilaments (MF) polymerization, and stress fibers (SF) assembly. Further investigation revealed that the Rho/ROCK signaling pathway regulated MF polymerization and SF assembly by facilitating the phosphorylation of cofilin and MLC, while Ca²⁺ chiefly governed SF assembly via MLC. Inhibiting α-SMA-MF-SF assembly changed Ang II-induced cell contraction, YAP nuclear translocation, and COL1A1 expression, findings corroborated in cirrhotic mice models. Overall, our study offers insights into mitigating IHVR and PH through cell mechanics, heralding potential breakthroughs.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151427"},"PeriodicalIF":6.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S017193352400044X/pdfft?md5=d0ffa0347f368a5f5bda649cec39f952&pid=1-s2.0-S017193352400044X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting F-actin stress fibers to suppress the dedifferentiated phenotype in chondrocytes","authors":"Mandy M. Schofield ,&nbsp;Alissa T. Rzepski ,&nbsp;Stephanie Richardson-Solorzano ,&nbsp;Jonah Hammerstedt ,&nbsp;Sohan Shah ,&nbsp;Chloe E. Mirack ,&nbsp;Marin Herrick ,&nbsp;Justin Parreno","doi":"10.1016/j.ejcb.2024.151424","DOIUrl":"10.1016/j.ejcb.2024.151424","url":null,"abstract":"<div><p>Actin is a central mediator of the chondrocyte phenotype. Monolayer expansion of articular chondrocytes on tissue culture polystyrene, for cell-based repair therapies, leads to chondrocyte dedifferentiation. During dedifferentiation, chondrocytes spread and filamentous (F-)actin reorganizes from a cortical to a stress fiber arrangement causing a reduction in cartilage matrix expression and an increase in fibroblastic matrix and contractile molecule expression. While the downstream mechanisms regulating chondrocyte molecular expression by alterations in F-actin organization have become elucidated, the critical upstream regulators of F-actin networks in chondrocytes are not completely known. Tropomyosin (TPM) and the RhoGTPases are known regulators of F-actin networks. The main purpose of this study is to elucidate the regulation of passaged chondrocyte F-actin stress fiber networks and cell phenotype by the specific TPM, TPM3.1, and the RhoGTPase, CDC42. Our results demonstrated that TPM3.1 associates with cortical F-actin and stress fiber F-actin in primary and passaged chondrocytes, respectively. In passaged cells, we found that pharmacological TPM3.1 inhibition or siRNA knockdown causes F-actin reorganization from stress fibers back to cortical F-actin and causes an increase in G/F-actin. CDC42 inhibition also causes formation of cortical F-actin. However, pharmacological CDC42 inhibition, but not TPM3.1 inhibition, leads to the re-association of TPM3.1 with cortical F-actin. Both TPM3.1 and CDC42 inhibition, as well as TPM3.1 knockdown, reduces nuclear localization of myocardin related transcription factor, which suppresses dedifferentiated molecule expression. We confirmed that TPM3.1 or CDC42 inhibition partially redifferentiates passaged cells by reducing fibroblast matrix and contractile expression, and increasing chondrogenic SOX9 expression. A further understanding on the regulation of F-actin in passaged cells may lead into new insights to stimulate cartilage matrix expression in cells for regenerative therapies.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151424"},"PeriodicalIF":6.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000414/pdfft?md5=b34dc391c5f6ee6137c475343b9955d5&pid=1-s2.0-S0171933524000414-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane localization of actin filaments stabilizes giant unilamellar vesicles against external deforming forces","authors":"Andreas Fink ,&nbsp;Sunnatullo Fazliev ,&nbsp;Tobias Abele ,&nbsp;Joachim P. Spatz ,&nbsp;Kerstin Göpfrich ,&nbsp;Elisabetta Ada Cavalcanti-Adam","doi":"10.1016/j.ejcb.2024.151428","DOIUrl":"10.1016/j.ejcb.2024.151428","url":null,"abstract":"<div><p>Actin organization is crucial for establishing cell polarity, which influences processes such as directed cell motility and division. Despite its critical role in living organisms, achieving similar polarity in synthetic cells remains challenging. In this study, we employ a bottom-up approach to investigate how molecular crowders facilitate the formation of cortex-like actin networks and how these networks localize and organize based on membrane shape. Using giant unilamellar vesicles (GUVs) as models for cell membranes, we show that actin filaments can arrange along the membrane to form cortex-like structures. Notably, this organization is achieved using only actin and crowders as a minimal set of components. We utilize surface micropatterning to examine actin filament organization in deformed GUVs adhered to various pattern shapes. Our findings indicate that at the periphery of spherical GUVs, actin bundles align along the membrane. However, in highly curved regions of adhered GUVs, actin bundles avoid crossing the highly curved edges perpendicular to the adhesion site and instead remain in the lower curved regions by aligning parallel to the micropatterned surface. Furthermore, the actin bundles increase the stiffness of the GUVs, effectively counteracting strong deformations when GUVs adhere to micropatterns. This finding is corroborated by real-time deformability cytometry on GUVs with synthetic actin cortices. By precisely manipulating the shape of GUVs, our study provides a minimal system to investigate the interplay between actin structures and the membrane. Our findings provide insights into the spatial organization of actin structures within crowded environments, specifically inside GUVs that resemble the size and shape of cells. This study advances our understanding of actin network organization and functionality within cell-sized compartments.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151428"},"PeriodicalIF":6.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000451/pdfft?md5=50716cf9eab95bdd5eeed968c7b7c752&pid=1-s2.0-S0171933524000451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141278415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The TRIP6/LATS1 complex constitutes the tension sensor of α-catenin/vinculin at both bicellular and tricellular junctions","authors":"Lin Xie ,&nbsp;Gangyun Wu ,&nbsp;Xiayu Liu ,&nbsp;Xiufen Duan ,&nbsp;Kaiyao Zhou ,&nbsp;Hua Li ,&nbsp;Wenxiu Ning","doi":"10.1016/j.ejcb.2024.151426","DOIUrl":"https://doi.org/10.1016/j.ejcb.2024.151426","url":null,"abstract":"<div><p>Cell-cell mechanotransduction regulates tissue development and homeostasis. α-catenin, the core component of adherens junctions, functions as a tension sensor and transducer by recruiting vinculin and transducing signals that influence cell behaviors. α-catenin/vinculin complex-mediated mechanotransduction regulates multiple pathways, such as Hippo pathway. However, their associations with the α-catenin-based tension sensors at cell junctions are still not fully addressed. Here, we uncovered the TRIP6/LATS1 complex co-localizes with α-catenin/vinculin at both bicellular junctions (BCJs) and tricellular junctions (TCJs). The localization of TRIP6/LATS1 complex to both TCJs and BCJs requires ROCK1 and α-catenin. Treatment by cytochalasin B, Y-27632 and blebbistatin all impaired the BCJ and TCJ junctional localization of TRIP6/LATS1, indicating that the junctional localization of TRIP6/LATS1 is mechanosensitive. The α-catenin/vinculin/TRIP6/LATS1 complex strongly localized to TCJs and exhibited a discontinuous button-like pattern on BCJs. Additionally, we developed and validated an α-catenin/vinculin BiFC-based mechanosensor that co-localizes with TRIP6/LATS1 at BCJs and TCJs. The mechanosensor exhibited a discontinuous distribution and motile signals at BCJs. Overall, our study revealed that TRIP6 and LATS1 are novel compositions of the tension sensor, together with the core complex of α-catenin/vinculin, at both the BCJs and TCJs.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151426"},"PeriodicalIF":6.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000438/pdfft?md5=4f9e2123cd493723f7610560642cb990&pid=1-s2.0-S0171933524000438-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicomponent depolymerization of actin filament pointed ends by cofilin and cyclase-associated protein depends upon filament age","authors":"Ekram M. Towsif,&nbsp;Blake Andrew Miller,&nbsp;Heidi Ulrichs,&nbsp;Shashank Shekhar","doi":"10.1016/j.ejcb.2024.151423","DOIUrl":"https://doi.org/10.1016/j.ejcb.2024.151423","url":null,"abstract":"<div><p>Intracellular actin networks assemble through the addition of ATP-actin subunits at the growing barbed ends of actin filaments. This is followed by “aging” of the filament via ATP hydrolysis and subsequent phosphate release. Aged ADP-actin subunits thus “treadmill” through the filament before being released back into the cytoplasmic monomer pool as a result of depolymerization at filament pointed ends. The necessity for aging before filament disassembly is reinforced by preferential binding of cofilin to aged ADP-actin subunits over newly-assembled ADP-P_i actin subunits in the filament. Consequently, investigations into how cofilin influences pointed-end depolymerization have, thus far, focused exclusively on aged ADP-actin filaments. Using microfluidics-assisted Total Internal Reflection Fluorescence (mf-TIRF) microscopy, we reveal that, similar to their effects on ADP filaments, cofilin and cyclase-associated protein (CAP) also promote pointed-end depolymerization of ADP-P_i filaments. Interestingly, the maximal rates of ADP-P_i filament depolymerization by CAP and cofilin together remain approximately 20–40 times lower than for ADP filaments. Further, we find that the promotion of ADP-P_i pointed-end depolymerization is conserved for all three mammalian cofilin isoforms. Taken together, the mechanisms presented here open the possibility of newly-assembled actin filaments being directly disassembled from their pointed-ends, thus bypassing the slow step of P_i release in the aging process.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151423"},"PeriodicalIF":6.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000402/pdfft?md5=ec5671fe282b4839686c7c4f655ec2a6&pid=1-s2.0-S0171933524000402-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation","authors":"Rohan Chippalkatti ,&nbsp;Bianca Parisi ,&nbsp;Farah Kouzi,&nbsp;Christina Laurini,&nbsp;Nesrine Ben Fredj,&nbsp;Daniel Kwaku Abankwa","doi":"10.1016/j.ejcb.2024.151425","DOIUrl":"https://doi.org/10.1016/j.ejcb.2024.151425","url":null,"abstract":"<div><p>The RAS-MAPK-pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While typically the impact of Ras on the proliferation of various cancer cell lines is assessed, it is poorly established how Ras affects cellular differentiation. Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that a minor pool of Pax7+ progenitors replenishes a major pool of transit amplifying cells that are ready to differentiate. Our data indicate that Ras isoforms have distinct roles in the differentiating culture, where K-Ras depletion increases and H-Ras depletion decreases terminal differentiation. This assay could therefore provide significant new insights into Ras biology and Ras-driven diseases. In line with this, we found that all oncogenic Ras mutants block terminal differentiation of transit amplifying cells. By contrast, RASopathy associated K-Ras variants were less able to block differentiation. Profiling of eight targeted Ras-pathway drugs on seven oncogenic Ras mutants revealed their allele-specific activities and distinct abilities to restore normal differentiation as compared to triggering cell death. In particular, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTOR-inhibitor rapamycin broadly suppressed differentiation. We expect that this quantitative assessment of the impact of Ras-pathway mutants and drugs on cellular differentiation has great potential to complement cancer cell proliferation data.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151425"},"PeriodicalIF":6.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000426/pdfft?md5=abbc8bc60cd0d77b37d2a3dc7a63f106&pid=1-s2.0-S0171933524000426-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide-dependent cell death in glioblastoma and squamous cell carcinoma via prodeath mitochondrial clustering","authors":"Yushi Ochiai ,&nbsp;Manami Suzuki-Karasaki ,&nbsp;Takashi Ando ,&nbsp;Miki Suzuki-Karasaki ,&nbsp;Hideki Nakayama ,&nbsp;Yoshihiro Suzuki-Karasaki","doi":"10.1016/j.ejcb.2024.151422","DOIUrl":"https://doi.org/10.1016/j.ejcb.2024.151422","url":null,"abstract":"<div><p>Besides the fission–fusion dynamics, the cellular distribution of mitochondria has recently emerged as a critical biological parameter in regulating mitochondrial function and cell survival. We previously found that mitochondrial clustering on the nuclear periphery, or monopolar perinuclear mitochondrial clustering (MPMC), accompanies the anticancer activity of air plasma-activated medium (APAM) against glioblastoma and human squamous cell carcinoma, which is closely associated with oxidant-dependent tubulin remodeling and mitochondrial fragmentation. Accordingly, this study investigated the regulatory roles of nitric oxide (NO) in the anticancer activity of APAM. Time-lapse analysis revealed a time-dependent increase in NO accompanied by MPMC. In contrast, APAM caused minimal increases in MPMC and NO levels in nontransformed cells. NO, hydroxyl radicals, and lipid peroxide levels increased near the damaged nuclear periphery, possibly within mitochondria. NO scavenging prevented tubulin remodeling, MPMC, perinuclear oxidant production, nuclear damage, and cell death. Conversely, synthetic NO donors augmented all the prodeath events and acted synergistically with APAM. Salinomycin, an emerging drug against multidrug-resistant cancers, had similar NO-dependent effects. These results suggest that APAM and salinomycin induce NO-dependent cell death, where MPMC and oxidative mitochondria play critical roles. Our findings encourage further investigations on MPMC as a potential target for NO-driven anticancer agents against drug-resistant cancers.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151422"},"PeriodicalIF":6.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000396/pdfft?md5=330f4a78143870839260f9c79403b24e&pid=1-s2.0-S0171933524000396-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitf, with Yki and STRIPAK-PP2A, is a key determinant of form and fate in the progenitor epithelium of the Drosophila eye.","authors":"Tianyi Zhang ,&nbsp;Qingxiang Zhou ,&nbsp;Nisveta Jusić ,&nbsp;Wenwen Lu ,&nbsp;Francesca Pignoni ,&nbsp;Scott J. Neal","doi":"10.1016/j.ejcb.2024.151421","DOIUrl":"10.1016/j.ejcb.2024.151421","url":null,"abstract":"<div><p>The Microphthalmia-associated Transcription Factor (MITF) governs numerous cellular and developmental processes. In mice, it promotes specification and differentiation of the retinal pigmented epithelium (RPE), and in humans, some mutations in MITF induce congenital eye malformations. Herein, we explore the function and regulation of Mitf in <em>Drosophila</em> eye development and uncover two roles. We find that knockdown of <em>Mitf</em> results in retinal displacement (RDis), a phenotype associated with abnormal eye formation. Mitf functions in the peripodial epithelium (PE), a retinal support tissue akin to the RPE, to suppress RDis, via the Hippo pathway effector Yorkie (Yki). Yki physically interacts with Mitf and can modify its transcriptional activity <em>in vitro</em>. Severe loss of Mitf, instead, results in the de-repression of retinogenesis in the PE, precluding its development. This activity of Mitf requires the protein phosphatase 2 A holoenzyme STRIPAK-PP2A, but not Yki; Mitf transcriptional activity is potentiated by STRIPAK-PP2A <em>in vitro</em> and <em>in vivo</em>. Knockdown of STRIPAK-PP2A results in cytoplasmic retention of Mitf <em>in vivo</em> and in its decreased stability <em>in vitro</em>, highlighting two potential mechanisms for the control of Mitf function by STRIPAK-PP2A. Thus, Mitf functions in a context-dependent manner as a key determinant of form and fate in the <em>Drosophila</em> eye progenitor epithelium.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151421"},"PeriodicalIF":6.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000384/pdfft?md5=4a8d8c5178cb796eea36268acf8caf2c&pid=1-s2.0-S0171933524000384-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141056221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear receptor Nur77 regulates immunomechanics of macrophages","authors":"Sanne C. Lith ,&nbsp;Tom M.J. Evers ,&nbsp;Beatriz Marton Freire ,&nbsp;Claudia M. van Tie ,&nbsp;Winnie. G. Vosa ,&nbsp;Alireza Mashaghi ,&nbsp;Carlie J.M. de Vries","doi":"10.1016/j.ejcb.2024.151419","DOIUrl":"10.1016/j.ejcb.2024.151419","url":null,"abstract":"<div><p>Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While cellular mechanics have been implicated in inflammation, the contribution of Nur77 to these mechanical processes remains elusive. Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. To establish the potential correlation of Nur77 with cellular mechanics, we compared bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Nur77-deficient (Nur77-KO) mice and employed cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis assays, and RNA-sequencing. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent <em>in vitro</em> experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics. Our findings suggest that immune regulation by Nur77 may be partially mediated through alterations in cellular mechanics, highlighting a potential avenue for therapeutic targeting.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151419"},"PeriodicalIF":6.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000360/pdfft?md5=575b7283c26b62adf52a1d283c8b48d0&pid=1-s2.0-S0171933524000360-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141046522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanoresponsive ETS1 causes endothelial dysfunction and arterialization in varicose veins via NOTCH4/DLL4 signaling","authors":"B.J. Sreelakshmi ,&nbsp;C.L. Karthika ,&nbsp;S. Ahalya ,&nbsp;S.R. Kalpana ,&nbsp;C.C. Kartha ,&nbsp;S. Sumi","doi":"10.1016/j.ejcb.2024.151420","DOIUrl":"10.1016/j.ejcb.2024.151420","url":null,"abstract":"<div><p>Varicose veins are the most common venous disorder in humans and are characterized by hemodynamic instability due to valvular insufficiency and orthostatic lifestyle factors. It is unclear how changes in biomechanical signals cause aberrant remodeling of the vein wall. Our previous studies suggest that Notch signaling is implicated in varicose vein arterialization. In the arterial system, mechanoresponsive ETS1 is a transcriptional activator of the endothelial Notch, but its involvement in sensing disrupted venous flow and varicose vein formation has not been investigated. Here, we use human varicose veins and cultured human venous endothelial cells to show that disturbed venous shear stress activates ETS1-NOTCH4/DLL4 signaling. Notch components were highly expressed in the neointima, whereas ETS1 was upregulated in all histological layers of varicose veins. <em>In vitro</em> microfluidic flow-based studies demonstrate that even minute changes in venous flow patterns enhance ETS1-NOTCH4/DLL4 signaling. Uniform venous shear stress, albeit an inherently low-flow system, does not induce ETS1 and Notch proteins. ETS1 activation under altered flow was mediated primarily by MEK1/2 and, to a lesser extent, by MEK5 but was independent of p38 MAP kinase. Endothelial cell-specific ETS1 knockdown prevented disturbed flow-induced NOTCH4/DLL4 expression. TK216, an inhibitor of ETS-family, prevented the acquisition of arterial molecular identity and loss of endothelial integrity in cells exposed to the ensuing altered shear stress. We conclude that ETS1 senses blood flow disturbances and may promote venous remodeling by inducing endothelial dysfunction. Targeting ETS1 rather than downstream Notch proteins could be an effective and safe strategy to develop varicose vein therapies.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 2","pages":"Article 151420"},"PeriodicalIF":6.6,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000372/pdfft?md5=930f260a21d087265164bb72c353f8c9&pid=1-s2.0-S0171933524000372-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}