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Pharmaceutics Nov 2022Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build... (Review)
Review
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.
PubMed: 36559113
DOI: 10.3390/pharmaceutics14122619 -
Journal of Cell Science Mar 2021Hippo signaling mediates influences of cytoskeletal tension on organ growth. TRIP6 and LIMD1 have each been identified as being required for tension-dependent inhibition...
Hippo signaling mediates influences of cytoskeletal tension on organ growth. TRIP6 and LIMD1 have each been identified as being required for tension-dependent inhibition of the Hippo pathway LATS kinases and their recruitment to adherens junctions, but the relationship between TRIP6 and LIMD1 was unknown. Using siRNA-mediated gene knockdown, we show that TRIP6 is required for LIMD1 localization to adherens junctions, whereas LIMD1 is not required for TRIP6 localization. TRIP6, but not LIMD1, is also required for the recruitment of vinculin and VASP to adherens junctions. Knockdown of TRIP6 or vinculin, but not of LIMD1, also influences the localization of myosin and F-actin. In TRIP6 knockdown cells, actin stress fibers are lost apically but increased basally, and there is a corresponding increase in the recruitment of vinculin and VASP to basal focal adhesions. Our observations identify a role for TRIP6 in organizing F-actin and maintaining tension at adherens junctions that could account for its influence on LIMD1 and LATS. They also suggest that focal adhesions and adherens junctions compete for key proteins needed to maintain attachments to contractile F-actin.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Cytoskeleton; Focal Adhesions; Vinculin
PubMed: 33558314
DOI: 10.1242/jcs.247866 -
Frontiers in Cell and Developmental... 2022Considerable progress has been made in our knowledge of the morphological and functional varieties of anchoring junctions. Cell-cell adhesion contacts consist of... (Review)
Review
Considerable progress has been made in our knowledge of the morphological and functional varieties of anchoring junctions. Cell-cell adhesion contacts consist of discrete junctional structures responsible for the mechanical coupling of cytoskeletons and allow the transmission of mechanical signals across the cell collective. The three main adhesion complexes are adherens junctions, tight junctions, and desmosomes. Microscopy has played a fundamental role in understanding these adhesion complexes on different levels in both physiological and pathological conditions. In this review, we discuss the main light and electron microscopy techniques used to unravel the structure and composition of the three cell-cell contacts in epithelial and endothelial cells. It functions as a guide to pick the appropriate imaging technique(s) for the adhesion complexes of interest. We also point out the latest techniques that have emerged. At the end, we discuss the problems investigators encounter during their cell-cell adhesion research using microscopic techniques.
PubMed: 35517500
DOI: 10.3389/fcell.2022.819534 -
F1000Research 2019The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete... (Review)
Review
The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete compartments. Four types of intercellular junction are present in vertebrates: desmosomes, adherens junctions, tight junctions, and gap junctions. All are essential for the development of the embryonic layers and organs as well as adult tissue homeostasis. While each junction type is defined as a distinct entity, it is now clear that they cooperate physically and functionally to create a robust and functionally diverse system. During evolution, desmosomes first appeared in vertebrates as highly specialized regions at the plasma membrane that couple the intermediate filament cytoskeleton at points of strong cell-cell adhesion. Here, we review how desmosomes conferred new mechanical and signaling properties to vertebrate cells and tissues through their interactions with the existing junctional and cytoskeletal network.
Topics: Animals; Cytoskeleton; Desmosomes; Intercellular Junctions; Signal Transduction
PubMed: 31942240
DOI: 10.12688/f1000research.20942.1 -
Cardiovascular Research Jun 2024SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) is a secreted or membrane-bound protein originally identified from endothelial cells...
AIMS
SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) is a secreted or membrane-bound protein originally identified from endothelial cells (ECs). Our previous work showed that SCUBE2 forms a complex with E-cadherin and stabilizes epithelial adherens junctions (AJs) to promote epithelial phenotypes. However, it remains unclear whether SCUBE2 also interacts with vascular endothelial (VE)-cadherin and modulates EC barrier function. In this study, we investigated whether and how SCUBE2 in ECs regulates vascular barrier maintenance.
METHODS AND RESULTS
We showed that SCUBE2 colocalized and interacted with VE-cadherin and VE-protein tyrosine phosphatase (VE-PTP) within EC AJs. Furthermore, SCUBE2 knockdown disrupted EC AJs and increased EC permeability. Expression of EC SCUBE2 was suppressed at both mRNA and protein levels via the nuclear factor-κB (NF-κB) signaling pathway in response to pro-inflammatory cytokines or permeability-inducing agents. In line with these findings, EC-specific deletion of Scube2 (EC-KO) in mice impaired baseline barrier function and worsened vascular leakiness of peripheral capillaries after local injection of histamine or vascular endothelial growth factor. EC-KO mice were also sensitive to pulmonary vascular hyperpermeability and leukocyte infiltration in response to acute endotoxin- or influenza virus-induced systemic inflammation. Meanwhile, EC-specific SCUBE2-overexpressing mice were protected from these effects. Molecular studies suggested that SCUBE2 acts as a scaffold molecule enabling VE-PTP to dephosphorylate VE-cadherin, which prevents VE-cadherin internalization and stabilizes EC AJs. As such, loss of SCUBE2 resulted in hyperphosphorylation of VE-cadherin at tyrosine 685, which led to its endocytosis, thus destabilizing EC AJs and reducing barrier function. All of these effects were exacerbated by inflammatory insults.
CONCLUSIONS
We found that SCUBE2 contributes to vascular integrity by recruiting VE-PTP to dephosphorylate VE-cadherin and stabilize AJs, thereby promoting EC barrier function. Moreover, our data suggest that genetic overexpression or pharmacological upregulation of SCUBE2 may help to prevent vascular leakage and edema in inflammatory diseases.
PubMed: 38870316
DOI: 10.1093/cvr/cvae132 -
Molecules (Basel, Switzerland) Jan 2022Diet-related obesity is associated with increased intestinal hyperpermeability. High dietary fat intake causes an increase in colonic bile acids (BAs), particularly...
Diet-related obesity is associated with increased intestinal hyperpermeability. High dietary fat intake causes an increase in colonic bile acids (BAs), particularly deoxycholic acid (DCA). We hypothesize that DCA modulates the gene expression of multiple cell junction pathways and increases intestinal permeability. With a human Caco-2 cell intestinal model, we used cell proliferation, PCR array, biochemical, and immunofluorescent assays to examine the impact of DCA on the integrity of the intestinal barrier and gene expression. The Caco-2 cells were grown in monolayers and challenged with DCA at physiological, sub-mM, concentrations. DCA increased transcellular and paracellular permeability (>20%). Similarly, DCA increased intracellular reactive oxidative species production (>100%) and accompanied a decrease (>40%) in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Moreover, the mRNA levels of 23 genes related to the epithelial barrier (tight junction, focal adhesion, gap junction, and adherens junction pathways) were decreased (>40%) in (0.25 mM) DCA-treated Caco-2 cells compared to untreated cells. Finally, we demonstrated that DCA decreased (>58%) the protein content of occludin present at the cellular tight junctions and the nucleus of epithelial cells. Collectively, DCA decreases the gene expression of multiple pathways related to cell junctions and increases permeability in a human intestinal barrier model.
Topics: Caco-2 Cells; Cell Proliferation; Cholagogues and Choleretics; Colon; Deoxycholic Acid; Gene Expression Regulation; Humans; Intercellular Junctions; Intestinal Mucosa; Permeability
PubMed: 35163990
DOI: 10.3390/molecules27030723 -
Investigative Ophthalmology & Visual... Aug 2023Lens transparency relies on the precise organization of lens fiber cells. The formation of the highly ordered lens architecture results from not only cell-cell adhesion...
PURPOSE
Lens transparency relies on the precise organization of lens fiber cells. The formation of the highly ordered lens architecture results from not only cell-cell adhesion along the lateral interfaces, but also from proper organization of fiber cells tips at lens sutures. Little is known about the cell adhesion between fiber tips at the sutures. The purpose of this study is to map suture-specific protein distributions.
METHODS
Tissue sections were obtained from fresh frozen bovine lenses and washes were performed to remove soluble proteins and to retain membrane and membrane associated proteins. Imaging mass spectrometry (IMS) combined with on-tissue trypsin digestion was used to visualize protein spatial distributions. Sutures and adjacent regions were captured by laser capture microdissection and samples were digested by trypsin. Proteins were analyzed by liquid chromatography tandem MS and quantified by label-free quantification. Protein spatial distributions were confirmed by immunofluorescence.
RESULTS
IMS results showed enrichment of adherens junction proteins cadherin-2 and armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) in both anterior and posterior sutures of bovine lenses. Liquid chromatography tandem MS confirmed higher expression of cadherin-2 and ARVCF and other adherens junction proteins including catenin α2 (CTNNA2) and catenin β1 (CTNNB1) in sutures. In contrast, IMS indicated low expression of gap junction protein connexin 50 and connexin 46 in the suture regions. The localization of cadherin-2 and connexin 50 was confirmed by immunofluorescence.
CONCLUSIONS
The complementary expression of adherens junction proteins and gap junction proteins in lens suture regions implicates adherens junctions in fiber cell tip adhesion and in maintaining the integrity of the lens.
Topics: Animals; Cattle; Proteomics; Trypsin; Intercellular Junctions; Cadherins; Catenins
PubMed: 37603353
DOI: 10.1167/iovs.64.11.28 -
Biochimica Et Biophysica Acta.... Sep 2020The apical junctional complex (AJC) is a cell-cell adhesion system present at the upper portion of the lateral membrane of epithelial cells integrated by the tight...
The apical junctional complex (AJC) is a cell-cell adhesion system present at the upper portion of the lateral membrane of epithelial cells integrated by the tight junction (TJ) and the adherens junction (AJ). This complex is crucial to initiate and stabilize cell-cell adhesion, to regulate the paracellular transit of ions and molecules and to maintain cell polarity. Moreover, we now consider the AJC as a hub of signal transduction that regulates cell-cell adhesion, gene transcription and cell proliferation and differentiation. The molecular components of the AJC are multiple and diverse and depending on the cellular context some of the proteins in this complex act as tumor suppressors or as promoters of cell transformation, migration and metastasis outgrowth. Here, we describe these new roles played by TJ and AJ proteins and their potential use in cancer diagnostics and as targets for therapeutic intervention.
Topics: Adherens Junctions; Cell Adhesion; Cell Differentiation; Cell Movement; Cell Polarity; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation; Humans; Intercellular Junctions; Neoplasms; Signal Transduction; Tight Junctions; Transcription, Genetic; Zonula Occludens-1 Protein
PubMed: 32240623
DOI: 10.1016/j.bbamem.2020.183278 -
BMC Genomic Data Aug 2023Sarcopenia is a disease diagnosed in the elderly. In patients with sarcopenia, the muscle mass decreases every year. The occurrence of sarcopenia is greatly affected by...
BACKGROUND
Sarcopenia is a disease diagnosed in the elderly. In patients with sarcopenia, the muscle mass decreases every year. The occurrence of sarcopenia is greatly affected by extrinsic factors such as eating habits, exercise, and lifestyle. The present study aimed to determine the relationship between muscle mass traits and genes affected by epigenetic factors with three different adjustment methods using Korean Genome and Epidemiology Study (KOGES) data.
RESULTS
We conducted a demographic study and DNA methylation profiling by three studies according to the muscle mass index (MMI) adjustment methods: appendicular skeletal muscle mass divided by body weight (MMI1); appendicular skeletal muscle mass divided by square of height (MMI2); appendicular skeletal muscle mass divided by BMI (MMI3). We analyzed differentially methylated regions (DMRs) for each group. We then restricted our subjects to be top 30% (T30) and bottom 30% (B30) based on each MMI adjustment method. Additionally, we performed enrichment analysis using PathfindR to evaluate the relationship between identified DMRs and sarcopenia. A total of 895 subjects were included in the demographic study. The values of BMI, waist, and hip showed a significant difference in all three groups. Among 446 participants, 44 subjects whose DNA methylation profiles were investigated were included for DNA methylation analysis. The results of enrichment analysis showed differences between groups. In the women group through MMI1 method, only the glutamatergic synapse pathway showed a significant result. In the men group through MMI2 method, the adherens junction pathway was the most significant. Women group through MMI2 method showed similar results, having an enriched Rap1 signaling pathway. In men group through MMI3 method, the Fc epsilon RI signaling pathway was the most enriched. Particularly, the notch signaling pathway was significantly enriched in women group through MMI3 method.
CONCLUSION
This study presents results about which factor should be concerned first in muscle mass index (MMI) adjustment. The present study suggested that GAB2 and JPH3 in MMI1 method, HLA-DQB1 and TBCD in MMI2 method, GAB2, NDUFB4 and ISPD in MMI3 method are potential genes that can have an impact on muscle mass. It could enable future epigenetic studies of genes based on annotation results. The present study is a nationwide study in Korea with the largest size up to date that compares adjustment indices for MMI in epigenetic research.
Topics: Aged; Female; Humans; Male; Adherens Junctions; DNA Methylation; Microtubule-Associated Proteins; Muscle, Skeletal; Sarcopenia
PubMed: 37653517
DOI: 10.1186/s12863-023-01152-3 -
Development (Cambridge, England) Dec 2020Planar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required...
Planar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required to establish PCP are poorly understood. Here, we identified a major role for the globular (G)-actin-binding protein thymosin-β4 (TMSB4X) in PCP establishment and cell adhesion in the developing epidermis. Depletion of in mouse embryos hindered eyelid closure and hair-follicle angling owing to PCP defects. depletion did not preclude epidermal cell adhesion or ; however, it resulted in abnormal structural organization and stability of adherens junction (AJ) due to defects in filamentous (F)-actin and G-actin distribution. In cultured keratinocytes, TMSB4X depletion increased the perijunctional G/F-actin ratio and decreased G-actin incorporation into junctional actin networks, but it did not change the overall actin expression level or cellular F-actin content. A pharmacological treatment that increased the G/F-actin ratio and decreased actin polymerization mimicked the effects of depletion on both AJs and PCP. Our results provide insights into the regulation of the actin pool and its involvement in AJ function and PCP establishment.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Animals; Cell Adhesion; Cell Polarity; Cell Shape; Embryonic Development; Epidermal Cells; Epidermis; Homeostasis; Keratinocytes; Mice; Microfilament Proteins; Morphogenesis; Thymosin
PubMed: 33310787
DOI: 10.1242/dev.193425