Mutant WASp stops cells in their tracks

Wiskott–Aldrich Syndrome (WAS) is a recessive disorder characterized by severe immunodeficiency. The gene responsible for WAS encodes a hematopoietic cell-specific protein, WASp, which has several binding sites for different actin regulatory molecules. How mutations in a potential actin-regulatory protein could affect immune function has been debated until recently. In the 17 August issue of Proceedings of the National Academy of Sciences, Linder et al. reported that WASp localizes to podosomes, the dynamic actin-containing adhesion structures formed by macrophages, monocytes, platelets, neutrophils, B cells and T cells that are necessary for chemotaxis. The figure shows part of a podosome structure formed by a primary human macrophage, localizing actin (red) and WASp (green), and areas of overlap (yellow). "Patients with WAS express very low levels of WASp," explained David Nelson, co-author on the study. The authors reported that macrophages taken from WAS patients could not assemble podosomes or respond normally to a bacterial chemoattractant. "Inability to form podosomes in hematopoietic cells probably causes defects in substrate adhesion and crawling, leading to immunodeficiency," said Nelson. The authors proposed that WASp functions by interacting with CDC42Hs, a member of the Rho family of GTPase-binding proteins, to control the formation of podosomes and other actin-based structures. Nelson added that this is one of the first known diseases caused by defects in cytoskeletal organization.