{"title":"Distinct molecular features of FLNC mutations, associated with different clinical phenotypes","authors":"Klimenko E.S, Zaytseva A.K, Sorokina M.Yu, Perepelina K.I, Rodina N.L, Nikitina E.G, Sukhareva K.S, Khudiakov A.A, Vershinina T.L, Muravyev A.S, Mikhaylov E.N, Pervunina T.M, Vasichkina E.S, Kostareva A.A","doi":"10.1002/cm.21922","DOIUrl":"10.1002/cm.21922","url":null,"abstract":"<p>Filamin С is a key an actin-binding protein of muscle cells playing a critical role in maintaining structural integrity and sarcomere organization. <i>FLNC</i> mutations contribute to various types of cardiomyopathies and myopathies through potentially different molecular mechanisms. Here, we described the impact of two clinically distinct <i>FLNC</i> variants (R1267Q associated with arrhythmogenic cardiomyopathy and V2264M associated with restrictive cardiomyopathy) on calcium homeostasis, electrophysiology, and gene expression profile of iPSC-derived patient-specific cardiomyocytes. We demonstrated that R1267Q <i>FLNC</i> variant leads to greater disturbances in calcium dynamics, Nav1.5 kinetics and action potentials compared to V2264M variant. These functional characteristics were accompanied by transcriptome changes in genes linked to action potential and sodium transport as well as structural cardiomyocyte genes. We suggest distinct molecular effects of two <i>FLNC</i> variants linked to different types of cardiomyopathies in terms of myofilament structure, electrophysiology, ion channel function and intracellular calcium homeostasis providing the molecular the bases for their different clinical phenotypes.</p>","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"82 3","pages":"158-174"},"PeriodicalIF":2.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cm.21922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-18DOI: 10.1002/cm.21928
Gülseren Özduman, Faruk Şimşek, Aadil Javed, Kemal Sami Korkmaz
{"title":"HN1 expression contributes to mitotic fidelity through Aurora A‐PLK1‐Eg5 axis","authors":"Gülseren Özduman, Faruk Şimşek, Aadil Javed, Kemal Sami Korkmaz","doi":"10.1002/cm.21928","DOIUrl":"https://doi.org/10.1002/cm.21928","url":null,"abstract":"Hematological and neurological expressed 1 (HN1) is homolog of Jupiter protein from <jats:italic>Drosophila melanogaster</jats:italic> where it functions as a microtubule‐associated protein. However, in mammalian cells, HN1 is associated partially with y‐tubulin in centrosomes, Stathmin for stabilizing microtubules, and Cdh1 for regulating Cyclin B1 for cell cycle regulation. Moreover, HN1 overexpression leads to early mitotic exit as well. Other molecular functions and interactions of HN1 are not clear yet. Here, based on our previous analysis where HN1 was shown to cluster supernumerary centrosomes and maintain mitotic spindle assembly, we further investigated the role of HN1 in centrosome maintenance and mitotic fidelity in PC‐3 prostate and MDA‐MB231 mammary cancer cell lines. The maturation‐associated roles of HN1 during cell division by examining the AuroraA‐PLK1 axis involving a plus end kinesin, Eg5 as well as pericentriolar matrix protein (PCM1) as components of centrosomes were established. We found that HN1 co‐localized to centrioles with Eg5 and Aurora A to suppress aberrant spindle formation to ensure the fidelity of centriole/centrosome duplication when overexpressed. Consistently, depleting the HN1 expression using siRNA or shRNA resulted in an increased number of dysregulated mitotic spindle structures, where Aurora A as well as PLK1 co‐localizations with Eg5 and PCM1 were disrupted. Further, the PLK1 and Aurora A kinase's phosphorylations also decreased, confirming the hypothesis that the cells struggle in mitotic progression, display nuclear and cytokinetic abnormalities with supernumerary but immature mononucleated centrosomes. In summary, we described the role of HN1 in centrosome nucleation/maturation in PLK1‐Eg5 axis and concomitant mitotic spindle formation in human cells.","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"52 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-14DOI: 10.1002/cm.21927
Bryan Demosthene, Pavlo Kravchuk, Connor L. Harmon, Abdulrazak Kalae, Ellen H. Kang
{"title":"Small organic osmolytes accelerate actin filament assembly and stiffen filaments","authors":"Bryan Demosthene, Pavlo Kravchuk, Connor L. Harmon, Abdulrazak Kalae, Ellen H. Kang","doi":"10.1002/cm.21927","DOIUrl":"https://doi.org/10.1002/cm.21927","url":null,"abstract":"Actin filament assembly and mechanics are crucial for maintenance of cell structure, motility, and division. Actin filament assembly occurs in a crowded intracellular environment consisting of various types of molecules, including small organic molecules known as osmolytes. Ample evidence highlights the protective functions of osmolytes such as trimethylamine‐N‐oxide (TMAO), including their effects on protein stability and their ability to counteract cellular osmotic stress. Yet, how TMAO affects individual actin filament assembly dynamics and mechanics is not well understood. We hypothesize that, owing to its protective nature, TMAO will enhance filament dynamics and stiffen actin filaments due to increased stability. In this study, we investigate osmolyte‐dependent actin filament assembly and bending mechanics by measuring filament elongation rates, steady‐state filament lengths, and bending persistence lengths in the presence of TMAO using total internal reflection fluorescence microscopy and pyrene assays. Our results demonstrate that TMAO increases filament elongation rates as well as steady‐state average filament lengths, and enhances filament bending stiffness. Together, these results will help us understand how small organic osmolytes modulate cytoskeletal protein assembly and mechanics in living cells.","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"33 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-12DOI: 10.1002/cm.21918
Noëmi Eva Linda Zimmermann
{"title":"Author profile: Noëmi Eva Linda Zimmermann","authors":"Noëmi Eva Linda Zimmermann","doi":"10.1002/cm.21918","DOIUrl":"10.1002/cm.21918","url":null,"abstract":"","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"81 11","pages":"693-694"},"PeriodicalIF":2.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-11DOI: 10.1002/cm.21913
Paul Trevorrow, Eva Karasmanis
{"title":"Introducing our Associate Editorial Board: An interview with Eva Karasmanis, University of San Diego, California, USA","authors":"Paul Trevorrow, Eva Karasmanis","doi":"10.1002/cm.21913","DOIUrl":"https://doi.org/10.1002/cm.21913","url":null,"abstract":"","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"252 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-06DOI: 10.1002/cm.21926
Aleksandr Dolskii, Sérgio A. Alcantara dos Santos, Mark Andrake, Janusz Franco-Barraza, Roland L. Dunbrack, Edna Cukierman
{"title":"Exploring the potential role of palladin in modulating human CAF/ECM functional units","authors":"Aleksandr Dolskii, Sérgio A. Alcantara dos Santos, Mark Andrake, Janusz Franco-Barraza, Roland L. Dunbrack, Edna Cukierman","doi":"10.1002/cm.21926","DOIUrl":"10.1002/cm.21926","url":null,"abstract":"<p>Fibroblasts, crucial for maintaining tissue homeostasis, significantly shape the tumor microenvironment (TME). In pancreatic cancer, a highly aggressive malignancy, cancer-associated fibroblast (CAF)/extracellular matrix (ECM) units dominate the TME, influencing tumor initiation, progression, and treatment responses. Palladin, an actin-associated protein, is vital for fibroblast structural integrity and activation, playing a key role in CAF/ECM functionality. Palladin interacts with cytoskeletal proteins such as alpha-actinin (α-Act) and can therefore regulate other proteins like syndecans, modulating cytoskeletal features, cell adhesion, integrin recycling, and signaling. In this review, we propose that targeting the palladin/α-Act/syndecan interaction network could modulate CAF/ECM units, potentially shifting the TME from a tumor-promoting to a tumor-suppressive state. In silico data and reported studies to suggest that stabilizing palladin-α-Act interactions, via excess palladin, influences syndecan functions; potentially modulating integrin endocytosis via syndecan engagement with protein kinase C alpha as opposed to syndecan binding to α-Act. This mechanism can then affect the distribution of active α5β1-integrin between the plasma membrane and known intracellular vesicular compartments, thereby influencing the tumor-suppressive versus tumor-promoting functions of CAF/ECM units. Understanding these interactions offers likely future therapeutic avenues for stroma normalization in pancreatic and other cancers, aiming to inhibit tumor progression and improve future treatment outcomes.</p>","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"82 3","pages":"175-185"},"PeriodicalIF":2.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytoskeletonPub Date : 2024-09-06DOI: 10.1002/cm.21925
Yaxin Li, Kangjing Li, Fumihiko Nakamura
{"title":"Characterization of open chromatin sensitive to actin polymerization and identification of core-binding factor subunit beta as mechanosensitive nucleocytoplasmic shuttling protein","authors":"Yaxin Li, Kangjing Li, Fumihiko Nakamura","doi":"10.1002/cm.21925","DOIUrl":"10.1002/cm.21925","url":null,"abstract":"<p>Mechanotransduction leads to a variety of biological responses including gene expression, changes in cell shape, migration, tissue development, and immune responses. Dysregulation of mechanotransduction is implicated in the progression of various diseases such as cardiovascular diseases and cancer. The actin cytoskeleton plays a crucial role in transmitting mechanical stimuli. Actin filaments, essential for cell motility and shape changes, respond to mechanical cues by remodeling, influencing gene expression via the linker of nucleoskeleton and cytoskeleton complex and mechanosensitive transcription factors. This study employs the dithiobis(succinimidyl propionate) (DSP)-micrococcal nuclease (MNase) proteogenomics method to explore the relationship between cellular mechanosensing, chromatin architecture, and the identification of proteins involved in mechanosensitive nucleocytoplasmic shuttling, revealing how actin polymerization affects chromatin and gene expression. We found that depolymerization of actin filaments by latrunculin B (Lat B) for 30 min is sufficient to alter open chromatin and identified core-binding factor subunit beta as mechanosensitive nucleocytoplasmic shuttling protein.</p>","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"82 4","pages":"260-269"},"PeriodicalIF":2.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}