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Plakophilin 3 and Par3 facilitate desmosomes' association with the apical junctional complex.

ABSTRACT: Desmosomes (DSMs), together with adherens junctions (AJs) and tight junctions (TJs), constitute the apical cell junctional complex (AJC). While the importance of the apical and basolateral polarity machinery in the organization of AJs and TJs is well established, how DSMs are positioned within the AJC is not understood. Here we use highly polarized DLD1 cells as a model to address how DSMs integrate into the AJC. We found that knockout (KO) of the desmosomal ARM protein Pkp3, but not other major DSM proteins, uncouples DSMs from the AJC without blocking DSM assembly. DLD1 cells also exhibit a prominent extraDSM pool of Pkp3, concentrated in tricellular (tC) contacts. Probing distinct apicobasal polarity pathways revealed that neither the DSM's association with AJC nor the extraDSM pool of Pkp3 are abolished in cells with defects in Scrib module proteins responsible for basolateral membrane development. However, a loss of the apical polarity protein, Par3, completely eliminates the extraDSM pool of Pkp3 and disrupts AJC localization of desmosomes, dispersing these junctions along the entire length of cell-cell contacts. Our data are consistent with a model whereby Par3 facilitates DSM assembly within the AJC, controlling the availability of an assembly competent pool of Pkp3 stored in tC contacts.

SUBMITTER: Indra I

PROVIDER: S-EPMC8684708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.

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Plakophilin 3 and Par3 facilitate desmosomes' association with the apical junctional complex.

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