A complex of Wiskott-Aldrich syndrome protein with mammalian verprolins plays an important role in monocyte chemotaxis.
The Wiskott-Aldrich syndrome protein (WASP) is a product of the gene defective in an Xid disorder, Wiskott-Aldrich syndrome. WASP expression is limited to hemopoietic cells, and WASP regulates the actin cytoskeleton. It has been reported that monocytes/macrophages from WASP-deficient Wiskott-Aldrich syndrome patients are severely defective in chemotaxis, resulting in recurrent infection. However, the molecular basis of such chemotactic defects is not understood. Recently, the WASP N-terminal region was found to bind to the three mammalian verprolin homologs: WASP interacting protein (WIP); WIP and CR16 homologous protein (WICH)/WIP-related protein (WIRE); and CR16. Verprolin was originally found to play an important role in the regulation of actin cytoskeleton in yeast. We have shown that WASP, WIP, and WICH/WIRE are expressed predominantly in the human monocyte cell line THP-1 and that WIP and WICH/WIRE are involved in monocyte chemotaxis. When WASP binding to verprolins was blocked, chemotactic migration of monocytes was impaired in both THP-1 cells and primary human monocytes. Increased expression of WASP and WIP enhanced monocyte chemotaxis. Blocking WASP binding to verprolins impaired cell polarization but not actin polymerization. These results indicate that a complex of WASP with mammalian verprolins plays an important role in chemotaxis of monocytes. Our results suggest that WASP and mammalian verprolins function as a unit in monocyte chemotaxis and that the activity of this unit is critical to establish cell polarization. In addition, our results also indicate that the WASP-verprolin complex is involved in other functions such as podosome formation and phagocytosis.
Tsuboi
Shigeru
S
Infectious and Inflammatory Disease Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA. stsuboi@burnham.org
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D010587:Phagocytosis; D011554:Pseudopodia / Q000378:metabolism; D020298:U937 Cells; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D002352:Carrier Proteins; D008840:Microfilament Proteins; C465744:WIPF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family