Tsuboi Shigeru, Meerloo Jennifer
Infectious and Inflammatory Disease Center and Cell Imaging Facility, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
J Biol Chem. 2007 Nov 23;282(47):34194-203. doi: 10.1074/jbc.M705999200. Epub 2007 Sep 21.
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. 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.
吞噬作用是机体抵御感染的重要一线防御机制，涉及由特殊细胞即吞噬细胞摄取和消化诸如细菌等外来物质。为了摄取外来物质，吞噬细胞在质膜处形成一种基于肌动蛋白的膜结构，称为吞噬杯。患有遗传性免疫缺陷疾病威斯科特-奥尔德里奇综合征（WAS）的患者的吞噬细胞中，吞噬杯的形成受损。WAS中缺陷的基因编码威斯科特-奥尔德里奇综合征蛋白（WASP）。WASP的突变或缺失导致吞噬杯形成受损，这表明WASP在吞噬杯形成中起重要作用。然而，其形成的分子细节仍不清楚。我们已经表明，WASP的C末端活性对巨噬细胞中吞噬杯的形成至关重要。我们证明，巨噬细胞中WASP在酪氨酸291处被磷酸化，且WASP的磷酸化对吞噬杯的形成很重要。此外，我们表明WASP和WASP相互作用蛋白（WIP）在吞噬杯处形成复合物，且WASP-WIP复合物在吞噬杯形成中起关键作用。我们的结果表明，WASP的磷酸化以及WASP与WIP的复合物形成是巨噬细胞中吞噬杯有效形成的基本分子步骤，这提示了WAS患者吞噬缺陷和反复感染潜在的疾病机制。
