Molecular Basis of Cell and Developmental Biology
FBP17 Mediates a Common Molecular Step in the Formation of Podosomes and Phagocytic Cups in Macrophages*

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Macrophages act to protect the body against inflammation and infection by engaging in chemotaxis and phagocytosis. In chemotaxis, macrophages use an actin-based membrane structure, the podosome, to migrate to inflamed tissues. In phagocytosis, macrophages form another type of actin-based membrane structure, the phagocytic cup, to ingest foreign materials such as bacteria. The formation of these membrane structures is severely affected in macrophages from patients with Wiskott-Aldrich syndrome (WAS), an X chromosome-linked immunodeficiency disorder. WAS patients lack WAS protein (WASP), suggesting that WASP is required for the formation of podosomes and phagocytic cups. Here we have demonstrated that formin-binding protein 17 (FBP17) recruits WASP, WASP-interacting protein (WIP), and dynamin-2 to the plasma membrane and that this recruitment is necessary for the formation of podosomes and phagocytic cups. The N-terminal EFC (extended FER-CIP4 homology)/F-BAR (FER-CIP4 homology and Bin-amphiphysin-Rvs) domain of FBP17 was previously shown to have membrane binding and deformation activities. Our results suggest that FBP17 facilitates membrane deformation and actin polymerization to occur simultaneously at the same membrane sites, which mediates a common molecular step in the formation of podosomes and phagocytic cups. These results provide a potential mechanism underlying the recurrent infections in WAS patients.

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The abbreviations used are: M-CSF-1, macrophage-colony stimulating factor-1; FBP17, formin-binding protein 17; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; N-WASP, neuronal WASP; WIP, WASP interacting-protein; EFC domain, extended FER-CIP4 homology domain; F-BAR domain, FER-CIP4 homology and Bin-amphiphysin-Rvs domain; PMA, phorbol 12-myristate 13-acetate; GFP, green fluorescence protein; siRNA, short interfering RNA; FITC, fluorescein isothiocyanate; PDZ-GEF, PDZ-guanine nucleotide exchange factor; HEK293 cells, human embryonic kidney 293 cells; HA, hemagglutinin; SH3, src homology 3 domain; dSH3, SH3 domain deletion; GST, glutathione S-transferase;, PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; siFBP, siRNA for FBP17; siC, scrambled control siRNA.

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This work was supported, in whole or in part, by National Institutes of Health Grant R01HD042752 (to S. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains six supplemental figures.