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SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis.

ABSTRACT: Actin plays a critical role during the early stages of pathogenic microbe internalization by immune cells. In this study, we identified a key mechanism of actin filament tethering and stabilization to the surface of phagosomes in human dendritic cells. We found that the actin-binding protein SWAP70 is specifically recruited to nascent phagosomes by binding to the lipid phosphatidylinositol (3,4)-bisphosphate. Multi-color super-resolution stimulated emission depletion (STED) microscopy revealed that the actin cage surrounding early phagosomes is formed by multiple concentric rings containing SWAP70. SWAP70 colocalized with and stimulated activation of RAC1, a known activator of actin polymerization, on phagosomes. Genetic ablation of SWAP70 impaired actin polymerization around phagosomes and resulted in a phagocytic defect. These data show a key role for SWAP70 as a scaffold for tethering the peripheral actin cage to phagosomes.

SUBMITTER: Baranov MV

PROVIDER: S-EPMC5149533 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis.

Baranov Maksim V MV Revelo Natalia H NH Dingjan Ilse I Maraspini Riccardo R Ter Beest Martin M Honigmann Alf A van den Bogaart Geert G

Cell reports 20161101 6

Actin plays a critical role during the early stages of pathogenic microbe internalization by immune cells. In this study, we identified a key mechanism of actin filament tethering and stabilization to the surface of phagosomes in human dendritic cells. We found that the actin-binding protein SWAP70 is specifically recruited to nascent phagosomes by binding to the lipid phosphatidylinositol (3,4)-bisphosphate. Multi-color super-resolution stimulated emission depletion (STED) microscopy revealed t ...[more]

PMID: 27806292

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Project description:Phagocytosis is a cellular process crucial for recognition and removal of apoptotic cells and foreign particles, subsequently initiating appropriate immune responses. The process of phagocytosis is highly complex and involves major rearrangements of the cytoskeleton. Due to its complexity and importance for tissue homoeostasis and immune responses, it is tightly regulated. Over the last decade, microRNAs (miRNAs) have emerged as important regulators of biological pathways including the immune response by fine-tuning expression of gene regulatory networks. In order to identify miRNAs implicated in the regulation of phagocytosis, a systematic screening of all currently known, human miRNAs was performed using THP-1 macrophage-like cells and serum-opsonized latex beads. Of the total of 2,566 miRNAs analyzed, several led to significant changes in phagocytosis. Among these, we validated miR-124-5p as a novel regulator of phagocytosis. Transfection with miR-124-5p mimics reduced the number of phagocytic cells as well as the phagocytic activity of phorbol-12-myristate-13-acetate (PMA)-activated THP-1 cells and ex vivo differentiated primary human macrophages. In silico analysis suggested that miR-124-5p targets genes involved in regulation of the actin cytoskeleton. Transcriptional analyses revealed that expression of genes encoding for several subunits of the ARP2/3 complex, a crucial regulator of actin polymerization, is reduced upon transfection of cells with miR-124-5p. Further in silico analyses identified potential binding motifs for miR-124-5p in the mRNAs of these genes. Luciferase reporter assays using these binding motifs indicate that at least two of the genes (ARPC3 and ARPC4) are direct targets of miR-124-5p. Moreover, ARPC3 and ARPC4 protein levels were significantly reduced following miR-124-5p transfection. Collectively, the presented results suggest that miR-124-5p regulates phagocytosis in human macrophages by directly targeting expression of components of the ARP2/3 complex.

Dataset Information

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis.

Publications

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis.

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