FBP17 Mediates a Common Molecular Step in the Formation of Podosomes and Phagocytic Cups in Macrophages.
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.
Tsuboi
Shigeru
S
Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. tsuboi@oyokyo.jp
Takada
Hidetoshi
H
Hara
Toshiro
T
Mochizuki
Naoki
N
Funyu
Tomihisa
T
Saitoh
Hisao
H
Terayama
Yuriko
Y
Yamaya
Kanemitsu
K
Ohyama
Chikara
C
Nonoyama
Shigeaki
S
Ochs
Hans D
HD
D000199:Actins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D021961:Cell Membrane Structures; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D034285:Dynamin II / Q000276:immunology / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000276:immunology / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C433770:FNBP1 protein, human; D050556:Fatty Acid-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C495767:WAS protein, human; C109903:WIPF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D034285:Dynamin II