International Immunology Advance Access originally published online on January 6, 2007
International Immunology 2007 19(2):185-192; doi:10.1093/intimm/dxl135
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The expression of Wiskott–Aldrich syndrome protein (WASP) is dependent on WASP-interacting protein (WIP)
1 Genetics and Molecular Biology Branch
2 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA
3 Present address: Yamagata Prefectural Central Hospital, Department of Pediatrics, 1800 Aoyagi, Oaza, Yamagata, Yamagata 990-2292, Japan
Correspondence to: F. Candotti; E-mail: fabio{at}nhgri.nih.gov
The Wiskott–Aldrich syndrome protein (WASP) is a key molecule for transduction of extracellular signals that induce a variety of critical biological events involving actin cytoskeleton rearrangement. Among the cellular partners of WASP, the Wiskott–Aldrich syndrome protein-interacting protein (WIP) has been speculated to play a critical role in the pathophysiology of Wiskott–Aldrich syndrome since WASP mutation hot spots map to the WIP-binding region. The notion that WIP promotes WASP function, however, conflicts with evidence that WIP inhibits WASP-mediated actin polymerization and IL-2 production and suggests a complex regulation of WASP function by WIP. Here we show that WASP gene transfer results in high WASP expression only when WIP is concomitantly expressed in K562 cells. Furthermore, WIP-knockdown experiments demonstrated that T cells with reduced WIP expression show a concordant reduction of WASP levels. Mapping studies using WIP mutants showed that the minimal WIP region able to rescue WASP expression in WIP-knockdown cells was the WASP-binding domain. However, expression of such a minimal domain of WIP failed to rescue WASP-dependent, nuclear factor of activated T-cells-mediated IL-2 transcriptional activity. These results demonstrate that expression of WIP is necessary for functional WASP expression in human cells and provide a new paradigm for understanding the function of these two molecules.
Keywords: post-translational regulation, Wiskott–Aldrich syndrome, Wiskott–Aldrich syndrome protein, Wiskott–Aldrich syndrome protein-interacting protein
Transmitting editor: W. Strober
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