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Keywords = adherens junction complex

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29 pages, 2426 KiB  
Review
Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases
by Buyan-Ochir Orgil, Mekaea S. Spaulding, Harrison P. Smith, Zainab Baba, Neely R. Alberson, Enkhzul Batsaikhan, Jeffrey A. Towbin and Enkhsaikhan Purevjav
Int. J. Mol. Sci. 2025, 26(14), 6856; https://doi.org/10.3390/ijms26146856 - 17 Jul 2025
Viewed by 296
Abstract
Transmembrane protein 43 (TMEM43 or LUMA) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction [...] Read more.
Transmembrane protein 43 (TMEM43 or LUMA) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. Genetic mutations may result in reduced TMEM43 expression and altered TMEM43 protein cellular localization, resulting in impaired cell polarization, intracellular force transmission, and cell–cell connections. The p.S358L mutation causes arrhythmogenic right ventricular cardiomyopathy type-5 and is associated with increased absorption of lipids, fatty acids, and cholesterol in the mouse small intestine, which may promote fibro-fatty replacement of cardiac myocytes. Mutations (p.E85K and p.I91V) have been identified in patients with Emery–Dreifuss Muscular Dystrophy-related myopathies. Other mutations also lead to auditory neuropathy spectrum disorder-associated hearing loss and have a negative association with cancer progression and tumor cell survival. This review explores the pathogenesis of TMEM43 mutation-associated diseases in humans, highlighting animal and in vitro studies that describe the molecular details of disease processes and clinical, histologic, and molecular manifestations. Additionally, we discuss TMEM43 expression-related conditions and how each disease may progress to severe and life-threatening states. Full article
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18 pages, 19397 KiB  
Article
Myofibroblast-like Cells and Junctional Complex Development Play a Role in Mouse Pubic Symphysis Remodeling During Pregnancy and Postpartum
by Viviane Souza Rosa, Bianca Gazieri Castelucci, Monica Moreira, Paulo Pinto Joazeiro and Sílvio Roberto Consonni
Int. J. Mol. Sci. 2025, 26(11), 5307; https://doi.org/10.3390/ijms26115307 - 31 May 2025
Viewed by 526
Abstract
During mouse pregnancy, the pubic symphysis (PS) undergoes a gradual transitioning into an interpubic ligament (IpL) for a successful delivery. After birth, this IpL is rapidly remodeled, returning to the non-pregnant morphology. The PS fibrocartilaginous cells acquire a myofibroblast-like phenotype, characterized by extracellular [...] Read more.
During mouse pregnancy, the pubic symphysis (PS) undergoes a gradual transitioning into an interpubic ligament (IpL) for a successful delivery. After birth, this IpL is rapidly remodeled, returning to the non-pregnant morphology. The PS fibrocartilaginous cells acquire a myofibroblast-like phenotype, characterized by extracellular matrix (ECM) secretion, expression of α-smooth muscle actin (α-SMA), and vimentin. While the presence of myofibroblast-like cells during the IpL remodeling is well described, cell–cell interactions and how this might contribute to the delivery remains poorly understood. This study uses ultrastructure and molecular approaches to investigate cell–cell and cell–ECM junctions during mouse pregnancy and postpartum. Our findings reveal that the intercellular contacts between adjacent IpL myofibroblast-like cells, particularly at late pregnancy stages, are characterized as adherens and GAP junctions. The acquisition of contractile elements by IpL cells, coupled with neighboring cells and the surrounding ECM via junctional complexes, suggests an important role in supporting changes in the mechanical forces generated by pubic bone movements during mouse pregnancy and also in tying the pelvic bones together, which may help the birth canal closure after delivery. Further studies in PS biology may investigate fibroblast to myofibroblast differentiation signaling cascades, which regulate the expression of pro-fibrotic proteins and may provide new insights for preterm labor. Full article
(This article belongs to the Special Issue Latest Advances in Reproduction Biology)
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16 pages, 2581 KiB  
Article
Loss of Cell-Cell Contact Inhibits Cellular Differentiation of α-Catenin Knock Out P19 Embryonal Carcinoma Cells and Their Colonization into the Developing Mouse Embryos
by Masahiro Sato, Emi Inada, Naoko Kubota and Masayuki Ozawa
BioTech 2024, 13(4), 41; https://doi.org/10.3390/biotech13040041 - 3 Oct 2024
Viewed by 2045
Abstract
Cadherin−catenin cell−cell adhesion complexes, composed of cadherin, β-catenin or plakoglobin, and α-catenin (α-cat) molecules, are crucial for maintaining cell−cell contact and are commonly referred to as “adherens junctions (AJs).” Inactivating this system leads to loss of cell−cell contact and developmental arrest in early [...] Read more.
Cadherin−catenin cell−cell adhesion complexes, composed of cadherin, β-catenin or plakoglobin, and α-catenin (α-cat) molecules, are crucial for maintaining cell−cell contact and are commonly referred to as “adherens junctions (AJs).” Inactivating this system leads to loss of cell−cell contact and developmental arrest in early embryos. However, it remains unclear whether the loss of cell−cell contact affects the differentiation of embryonic cells. In this study, we explored the use of a murine embryonal carcinoma cell line, P19, as an in vitro model for early embryogenesis. P19 cells easily form embryoid bodies (EBs) and are susceptible to cellular differentiation in response to retinoic acid (RA) and teratoma formation. Using CRISPR/Cas9 technology to disrupt the endogenous α-cat gene in P19 cells, we generated α-cat knockout (KO) cells that exhibited a loss of cell−cell contact. When cultivated on non-coated dishes, these α-cat KO cells formed EBs, but their structures were labile. In the RA-containing medium, the α-cat KO EBs failed to produce differentiated cells on their outer layer and continued to express SSEA-1, an antigen specific to pluripotent cells. Teratoma formation assays revealed an absence of overt differentiated cells in tumors derived from α-cat KO P19 cells. Aggregation assays revealed the inability of the KO cells to colonize into the zona pellucida-denuded 8-cell embryos. These findings suggest that the AJs are essential for promoting the early stages of cellular differentiation and for the colonization of early-developing embryos. Full article
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18 pages, 10203 KiB  
Article
Single-Cell RNA Sequencing Reveals an Atlas of Hezuo Pig Testis Cells
by Zunqiang Yan, Pengfei Wang, Qiaoli Yang and Shuangbao Gun
Int. J. Mol. Sci. 2024, 25(18), 9786; https://doi.org/10.3390/ijms25189786 - 10 Sep 2024
Cited by 2 | Viewed by 2357
Abstract
Spermatogenesis is a complex biological process crucial for male reproduction and is characterized by intricate interactions between testicular somatic cells and germ cells. Due to the cellular heterogeneity of the testes, investigating different cell types across developmental stages has been challenging. Single-cell RNA [...] Read more.
Spermatogenesis is a complex biological process crucial for male reproduction and is characterized by intricate interactions between testicular somatic cells and germ cells. Due to the cellular heterogeneity of the testes, investigating different cell types across developmental stages has been challenging. Single-cell RNA sequencing (scRNA-seq) has emerged as a valuable approach for addressing this limitation. Here, we conducted an unbiased transcriptomic study of spermatogenesis in sexually mature 4-month-old Hezuo pigs using 10× Genomics-based scRNA-seq. A total of 16,082 cells were collected from Hezuo pig testes, including germ cells (spermatogonia (SPG), spermatocytes (SPCs), spermatids (SPTs), and sperm (SP)) and somatic cells (Sertoli cells (SCs), Leydig cells (LCs), myoid cells (MCs), endothelial cells (ECs), and natural killer (NK) cells/macrophages). Pseudo-time analysis revealed that LCs and MCs originated from common progenitors in the Hezuo pig. Functional enrichment analysis indicated that the differentially expressed genes (DEGs) in the different types of testicular germ cells were enriched in the PI3K–AKT, Wnt, HIF-1, and adherens junction signaling pathways, while the DEGs in testicular somatic cells were enriched in ECM–receptor interaction and antigen processing and presentation. Moreover, genes related to spermatogenesis, male gamete generation, sperm part, sperm flagellum, and peptide biosynthesis were expressed throughout spermatogenesis. Using immunohistochemistry, we verified several stage-specific marker genes (such as UCHL1, WT1, SOX9, and ACTA2) for SPG, SCs, and MCs. By exploring the changes in the transcription patterns of various cell types during spermatogenesis, our study provided novel insights into spermatogenesis and testicular cells in the Hezuo pig, thereby laying the foundation for the breeding and preservation of this breed. Full article
(This article belongs to the Section Molecular Biology)
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24 pages, 1458 KiB  
Review
Nanoparticles and Airway Epithelial Cells: Exploring the Impacts and Methodologies in Toxicity Assessment
by Claire E. Lee and Fariba Rezaee
Int. J. Mol. Sci. 2024, 25(14), 7885; https://doi.org/10.3390/ijms25147885 - 18 Jul 2024
Viewed by 2465
Abstract
The production of nanoparticles has recently surged due to their varied applications in the biomedical, pharmaceutical, textile, and electronic sectors. However, this rapid increase in nanoparticle manufacturing has raised concerns about environmental pollution, particularly its potential adverse effects on human health. Among the [...] Read more.
The production of nanoparticles has recently surged due to their varied applications in the biomedical, pharmaceutical, textile, and electronic sectors. However, this rapid increase in nanoparticle manufacturing has raised concerns about environmental pollution, particularly its potential adverse effects on human health. Among the various concerns, inhalation exposure to nanoparticles poses significant risks, especially affecting the respiratory system. Airway epithelial cells play a crucial role as the primary defense against inhaled particulate matter and pathogens. Studies have shown that nanoparticles can disrupt the airway epithelial barrier, triggering inflammatory responses, generating reactive oxygen species, and compromising cell viability. However, our understanding of how different types of nanoparticles specifically impact the airway epithelial barrier remains limited. Both in vitro cell culture and in vivo murine models are commonly utilized to investigate nanoparticle-induced cellular responses and barrier dysfunction. This review discusses the methodologies frequently employed to assess nanoparticle toxicity and barrier disruption. Furthermore, we analyze and compare the distinct effects of various nanoparticle types on the airway epithelial barrier. By elucidating the diverse responses elicited by different nanoparticles, we aim to provide insights that can guide future research endeavors in assessing and mitigating the potential risks associated with nanoparticle exposure. Full article
(This article belongs to the Special Issue Molecular Research of Epithelial Function and Barrier Dysfunction)
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18 pages, 2348 KiB  
Article
Helicobacter pylori-Induced Decrease in Membrane Expression of Na,K-ATPase Leads to Gastric Injury
by Olga Vagin, Elmira Tokhtaeva, Muriel Larauche, Joshua Davood and Elizabeth A. Marcus
Biomolecules 2024, 14(7), 772; https://doi.org/10.3390/biom14070772 - 28 Jun 2024
Viewed by 1640
Abstract
Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been [...] Read more.
Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been shown to be important for maintaining the barrier function of lung and kidney epithelia. H. pylori decreases levels of Na,K-ATPase in the plasma membrane of gastric epithelial cells, and the aim of this study was to demonstrate that this reduction led to gastric injury by impairing the epithelial barrier. Similar to H. pylori infection, the inhibition of Na,K-ATPase with ouabain decreased transepithelial electrical resistance and increased paracellular permeability in cell monolayers of human gastric cultured cells, 2D human gastric organoids, and gastric epithelium isolated from gerbils. Similar effects were caused by a partial shRNA silencing of Na,K-ATPase in human gastric organoids. Both H. pylori infection and ouabain exposure disrupted organization of adherens junctions in human gastric epithelia as demonstrated by E-cadherin immunofluorescence. Functional and structural impairment of epithelial integrity with a decrease in Na,K-ATPase amount or activity provides evidence that the H. pylori-induced downregulation of Na,K-ATPase plays a role in the complex mechanism of gastric disease induced by the bacteria. Full article
(This article belongs to the Special Issue The Role of P-type ATPases in Health and Diseases)
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20 pages, 12848 KiB  
Article
Actin Cytoskeleton Remodeling Accompanied by Redistribution of Adhesion Proteins Drives Migration of Cells in Different EMT States
by Alla S. Ilnitskaya, Nikita I. Litovka, Svetlana N. Rubtsova, Irina Y. Zhitnyak and Natalya A. Gloushankova
Cells 2024, 13(9), 780; https://doi.org/10.3390/cells13090780 - 2 May 2024
Cited by 3 | Viewed by 3063
Abstract
Epithelial–mesenchymal transition (EMT) is a process during which epithelial cells lose epithelial characteristics and gain mesenchymal features. Here, we used several cell models to study migratory activity and redistribution of cell–cell adhesion proteins in cells in different EMT states: EGF-induced EMT of epithelial [...] Read more.
Epithelial–mesenchymal transition (EMT) is a process during which epithelial cells lose epithelial characteristics and gain mesenchymal features. Here, we used several cell models to study migratory activity and redistribution of cell–cell adhesion proteins in cells in different EMT states: EGF-induced EMT of epithelial IAR-20 cells; IAR-6-1 cells with a hybrid epithelial–mesenchymal phenotype; and their more mesenchymal derivatives, IAR-6-1-DNE cells lacking adherens junctions. In migrating cells, the cell–cell adhesion protein α-catenin accumulated at the leading edges along with ArpC2/p34 and α-actinin. Suppression of α-catenin shifted cell morphology from fibroblast-like to discoid and attenuated cell migration. Expression of exogenous α-catenin in MDA-MB-468 cells devoid of α-catenin drastically increased their migratory capabilities. The Y654 phosphorylated form of β-catenin was detected at integrin adhesion complexes (IACs). Co-immunoprecipitation studies indicated that α-catenin and pY654-β-catenin were associated with IAC proteins: vinculin, zyxin, and α-actinin. Taken together, these data suggest that in cells undergoing EMT, catenins not participating in assembly of adherens junctions may affect cell migration. Full article
(This article belongs to the Special Issue Cytoskeletal Remodeling in Health and Disease)
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32 pages, 1768 KiB  
Review
Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones
by Susana Lechuga, Armando Marino-Melendez, Nayden G. Naydenov, Atif Zafar, Manuel B. Braga-Neto and Andrei I. Ivanov
Cells 2024, 13(5), 370; https://doi.org/10.3390/cells13050370 - 21 Feb 2024
Cited by 3 | Viewed by 3422
Abstract
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction–cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known [...] Read more.
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction–cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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17 pages, 1409 KiB  
Review
Calpain Regulation and Dysregulation—Its Effects on the Intercalated Disk
by Micah W. Yoder, Nathan T. Wright and Maegen A. Borzok
Int. J. Mol. Sci. 2023, 24(14), 11726; https://doi.org/10.3390/ijms241411726 - 21 Jul 2023
Cited by 4 | Viewed by 2336
Abstract
The intercalated disk is a cardiac specific structure composed of three main protein complexes—adherens junctions, desmosomes, and gap junctions—that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. [...] Read more.
The intercalated disk is a cardiac specific structure composed of three main protein complexes—adherens junctions, desmosomes, and gap junctions—that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. Calpain proteases, a class of cysteine proteases dependent on calcium for activation, have recently emerged as important regulators of individual intercalated disk components. In this review, we will examine how calcium homeostasis regulates normal calpain function. We will also explore how calpains modulate gap junctions, desmosomes, and adherens junctions activity by targeting specific proteins, and describe the molecular mechanisms of how calpain dysregulation leads to structural and signaling defects within the heart. We will then examine how changes in calpain activity affects cardiomyocytes, and how such changes underlie various heart diseases. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease)
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17 pages, 2067 KiB  
Review
The Rare Marine Bioactive Compounds in Neurological Disorders and Diseases: Is the Blood-Brain Barrier an Obstacle or a Target?
by Xiaozhen Diao, Hui Han, Bailin Li, Zhen Guo, Jun Fu and Wenhui Wu
Mar. Drugs 2023, 21(7), 406; https://doi.org/10.3390/md21070406 - 18 Jul 2023
Cited by 7 | Viewed by 3528
Abstract
The blood-brain barrier (BBB) is a dynamic barrier separating neurocytes and brain tissues from blood that is extremely sealed and strictly regulated by transporters such as aquaporin-4 (AQP-4), glucose transporter (GLUT), and specialized tight junctional complexes (TJCs) including tight junctions (TJs), adherens junctions [...] Read more.
The blood-brain barrier (BBB) is a dynamic barrier separating neurocytes and brain tissues from blood that is extremely sealed and strictly regulated by transporters such as aquaporin-4 (AQP-4), glucose transporter (GLUT), and specialized tight junctional complexes (TJCs) including tight junctions (TJs), adherens junctions (AJs), and Zonulae occludens (ZOs). With specifically selective transcellular and paracellular permeability, the BBB maintains a homeostatic microenvironment to protect the central nervous system (CNS). In recent years, increasing attention has been paied to the importance of BBB disruption and dysfunction in the pathology of neurological disorders and diseases, such as Alzheimer’s diseases (AD), Parkinson diseases (PD), stroke and cerebral edema. However, the further research on how the integral structure and function of BBB are altered under the physiological or pathological conditions is still needed. Focusing on the ultrastructural features of the BBB and combining the latest research on associated proteins and transporters, physiological regulation and pathological change of the BBB were elucidated. By summarizing the protective effects of known bioactive compounds derived from marine life on the BBB, this review aims to highlight the BBB as a key to the treatment of several major neurological diseases instead of a normally described obstacle to drug absorption and transport. Overall, the BBB’s morphological characteristics and physiological function and their regulation provide the theoretical basis for the study on the BBB and inspire the diagnosis of and therapy for neurological diseases. Full article
(This article belongs to the Special Issue Perspectives for the Development of New Multitarget Marine Drugs)
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19 pages, 893 KiB  
Review
CmPn/CmP Signaling Networks in the Maintenance of the Blood Vessel Barrier
by Revathi Gnanasekaran, Justin Aickareth, Majd Hawwar, Nickolas Sanchez, Jacob Croft and Jun Zhang
J. Pers. Med. 2023, 13(5), 751; https://doi.org/10.3390/jpm13050751 - 28 Apr 2023
Cited by 5 | Viewed by 3215
Abstract
Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood–brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) [...] Read more.
Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood–brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood–brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood–brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs). Full article
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18 pages, 7734 KiB  
Article
IL-33 via PKCμ/PRKD1 Mediated α-Catenin Phosphorylation Regulates Endothelial Cell-Barrier Integrity and Ischemia-Induced Vascular Leakage
by Deepti Sharma, Geetika Kaur, Shivantika Bisen, Anamika Sharma, Ahmed S. Ibrahim and Nikhlesh K. Singh
Cells 2023, 12(5), 703; https://doi.org/10.3390/cells12050703 - 23 Feb 2023
Cited by 5 | Viewed by 2899
Abstract
Angiogenesis, neovascularization, and vascular remodeling are highly dynamic processes, where endothelial cell–cell adhesion within the vessel wall controls a range of physiological processes, such as growth, integrity, and barrier function. The cadherin–catenin adhesion complex is a key contributor to inner blood–retinal barrier (iBRB) [...] Read more.
Angiogenesis, neovascularization, and vascular remodeling are highly dynamic processes, where endothelial cell–cell adhesion within the vessel wall controls a range of physiological processes, such as growth, integrity, and barrier function. The cadherin–catenin adhesion complex is a key contributor to inner blood–retinal barrier (iBRB) integrity and dynamic cell movements. However, the pre-eminent role of cadherins and their associated catenins in iBRB structure and function is not fully understood. Using a murine model of oxygen-induced retinopathy (OIR) and human retinal microvascular endothelial cells (HRMVECs), we try to understand the significance of IL-33 on retinal endothelial barrier disruption, leading to abnormal angiogenesis and enhanced vascular permeability. Using electric cell-substrate impedance sensing (ECIS) analysis and FITC-dextran permeability assay, we observed that IL-33 at a 20 ng/mL concentration induced endothelial-barrier disruption in HRMVECs. The adherens junction (AJs) proteins play a prominent role in the selective diffusion of molecules from the blood to the retina and in maintaining retinal homeostasis. Therefore, we looked for the involvement of adherens junction proteins in IL-33-mediated endothelial dysfunction. We observed that IL-33 induces α-catenin phosphorylation at serine/threonine (Ser/Thr) residues in HRMVECs. Furthermore, mass-spectroscopy (MS) analysis revealed that IL-33 induces the phosphorylation of α-catenin at Thr654 residue in HRMVECs. We also observed that PKCμ/PRKD1-p38 MAPK signaling regulates IL-33-induced α-catenin phosphorylation and retinal endothelial cell-barrier integrity. Our OIR studies revealed that genetic deletion of IL-33 resulted in reduced vascular leakage in the hypoxic retina. We also observed that the genetic deletion of IL-33 reduced OIR-induced PKCμ/PRKD1-p38 MAPK-α-catenin signaling in the hypoxic retina. Therefore, we conclude that IL-33-induced PKCμ/PRKD1-p38 MAPK-α-catenin signaling plays a significant role in endothelial permeability and iBRB integrity. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Retinal Diseases)
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32 pages, 1245 KiB  
Review
Airway Epithelial Cell Junctions as Targets for Pathogens and Antimicrobial Therapy
by Nannan Gao and Fariba Rezaee
Pharmaceutics 2022, 14(12), 2619; https://doi.org/10.3390/pharmaceutics14122619 - 27 Nov 2022
Cited by 21 | Viewed by 5878
Abstract
Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build epithelial barriers to pathogens, inhaled allergens, and environmental particles in the respiratory tract. AJCs consist of tight junctions (TJs) and adherens junctions [...] Read more.
Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build epithelial barriers to pathogens, inhaled allergens, and environmental particles in the respiratory tract. AJCs consist of tight junctions (TJs) and adherens junctions (AJs), which play a key role in maintaining the integrity of the airway barrier. Emerging evidence has shown that different microorganisms cause airway barrier dysfunction by targeting TJ and AJ proteins. This review discusses the pathophysiologic mechanisms by which several microorganisms (bacteria and viruses) lead to the disruption of AJCs in airway epithelial cells. We present recent progress in understanding signaling pathways involved in the formation and regulation of cell junctions. We also summarize the potential chemical inhibitors and pharmacological approaches to restore the integrity of the airway epithelial barrier. Understanding the AJCs–pathogen interactions and mechanisms by which microorganisms target the AJC and impair barrier function may further help design therapeutic innovations to treat these infections. Full article
(This article belongs to the Special Issue Targeting Cell Junctions for Therapy and Delivery)
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20 pages, 4087 KiB  
Article
ECM Substrates Impact RNAi Localization at Adherens Junctions of Colon Epithelial Cells
by Amanda C. Daulagala and Antonis Kourtidis
Cells 2022, 11(23), 3740; https://doi.org/10.3390/cells11233740 - 23 Nov 2022
Cited by 6 | Viewed by 2701
Abstract
The extracellular matrix (ECM) plays crucial roles in tissue homeostasis. Abnormalities in ECM composition are associated with pathological conditions, such as fibrosis and cancer. These ECM alterations are sensed by the epithelium and can influence its behavior through crosstalk with other mechanosensitive complexes, [...] Read more.
The extracellular matrix (ECM) plays crucial roles in tissue homeostasis. Abnormalities in ECM composition are associated with pathological conditions, such as fibrosis and cancer. These ECM alterations are sensed by the epithelium and can influence its behavior through crosstalk with other mechanosensitive complexes, including the adherens junctions (AJs). We have previously shown that the AJs, through their component PLEKHA7, recruit the RNAi machinery to regulate miRNA levels and function. We have particularly shown that the junctional localization of RNAi components is critical for their function. Here, we investigated whether different ECM substrates can influence the junctional localization of RNAi complexes. To do this, we plated colon epithelial Caco2 cells on four key ECM substrates found in the colon under normal or pathogenic conditions, namely laminin, fibronectin, collagen I, and collagen IV, and we examined the subcellular distribution of PLEKHA7, and of the key RNAi components AGO2 and DROSHA. Fibronectin and collagen I negatively impacted the junctional localization of PLEKHA7, AGO2, and DROSHA when compared to laminin. Furthermore, fibronectin, collagen I, and collagen IV disrupted interactions of AGO2 and DROSHA with their essential partners GW182 and DGCR8, respectively, both at AJs and throughout the cell. Combinations of all substrates with fibronectin also negatively impacted junctional localization of PLEKHA7 and AGO2. Additionally, collagen I triggered accumulation of DROSHA at tri-cellular junctions, while both collagen I and collagen IV resulted in DROSHA accumulation at basal areas of cell–cell contact. Altogether, fibronectin and collagens I and IV, which are elevated in the stroma of fibrotic and cancerous tissues, altered localization patterns and disrupted complex formation of PLEKHA7 and RNAi components. Combined with our prior studies showing that apical junctional localization of the PLEKHA7-RNAi complex is critical for regulating tumor-suppressing miRNAs, this work points to a yet unstudied mechanism that could contribute to epithelial cell transformation. Full article
(This article belongs to the Special Issue MicroRNAs in Cancer: Biomarkers, Functions and Therapies)
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15 pages, 2666 KiB  
Article
Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
by Márcia Faria, José Vareda, Micaella Miranda, Maria João Bugalho, Ana Luísa Silva and Paulo Matos
Cancers 2022, 14(21), 5362; https://doi.org/10.3390/cancers14215362 - 31 Oct 2022
Cited by 6 | Viewed by 2223
Abstract
While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness [...] Read more.
While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells’ PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell–cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell–cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell–cell adhesion and NIS PM retention in refractory TC cells. Full article
(This article belongs to the Special Issue Thyroid Carcinoma)
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