Wiskott-aldrich syndrome protein is a key regulator of the phagocytic cup formation in macrophages

Tsuboi S, Meerloo J
Source: J Biol Chem
Publication Date: (2007)
Issue: 282(47): 34194-203
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Species: human
Tissue Origin: blood
Macrophage, human
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
Phagocytosis is a vital first-line host defense mechanism against infection, involving the ingestion and digestion of foreign materials such as bacteria by specialized cells, phagocytes. In order for phagocytes to ingest the foreign materials, they form an actin-based membrane structure called phagocytic cup at the plasma membranes. Formation of the phagocytic cup is impaired in phagocytes from patients with a genetic immunodeficiency disorder, Wiskott-Aldrich syndrome (WAS). The gene defective in WAS encodes Wiskott-Aldrich syndrome protein (WASP). Mutation or deletion of WASP causes impaired formation of the phagocytic cup, suggesting that WASP plays an important role in the phagocytic cup formation. However, the molecular details of its formation remain unknown. We have shown that the WASP C-terminal activity is critical for the phagocytic cup formation in macrophages. We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASP interacting protein (WIP) form a complex at the phagocytic cup and that the WASP-WIP complex plays a critical role in the phagocytic cup formation. Our results indicate that the phosphorylation of WASP and the complex formation of WASP with WIP are the essential molecular steps for the efficient formation of the phagocytic cup in macrophages, suggesting a possible disease mechanism underlying phagocytic defects and recurrent infections in WAS patients.