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Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, CA 92037
Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.
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1 This work was supported by National Institutes of Health Grant R01 HD42752.
2 Address correspondence and reprint requests to Dr. Shigeru Tsuboi, Infectious Disease Program, Infectious and Inflammatory Disease Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: stsuboi{at}burnham.org
3 Abbreviations used in this paper: WAS, Wiskott-Aldrich syndrome; Arp2/3, actin-related protein 2/3 (complex); dW, WASP deletion mutant; F-C, FLAG-tagged PDZ-GEF C-terminal fragment; F-mW, FLAG-tagged mouse WASP cDNA; F-WB, FLAG-tagged WASP binding site of WIP; GBD, GTPase binding domain; M-42, Myc-tagged V12Cdc42; M-C, Myc-tagged PDZ-GEF as control; M-WN, Myc-tagged WASP N-terminal fragment; PDZ-GEF, PDZ-guanine nucleotide exchange factor; siRNA, small interfering RNA; WASP, WAS protein; WB, WASP binding (domain); WICH, WIP and CR16 homologous protein; VCA, verprolin/cofilin/acidic (domain); WIP, WASP-interacting protein; WIRE, WIP-related protein; XLT, X-linked thrombocytopenia.
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