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The Wiskott-Aldrich Syndrome Protein Regulates Nuclear Translocation of NFAT2 and NF-B (RelA) Independently of Its Role in Filamentous Actin Polymerization and Actin Cytoskeletal Rearrangement¹

Winifred Huang^*, Hans D. Ochs, Bo Dupont and Yatin M. Vyas^2,*

^* Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, and Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10021; and Department of Pediatrics, University of Washington, Seattle, WA 98195

Effector functions mediated by NK cells involve cytotoxicity and transcription-dependent production and release of cytokines and chemokines. Although the JAK/STAT pathway mediates lymphokine-induced transcriptional regulation in NK cells, very little is known about transcriptional regulation induced during cell-cell contact. We demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an important component for integration of signals leading to nuclear translocation of NFAT2 and NF-B (RelA) during cell-cell contact and NKp46-dependent signaling. This WASp function is independent of its known role in F-actin polymerization and cytoskeletal rearrangement. Absence of WASp results in decreased accumulation of calcineurin, WASp-interacting protein, and molecules upstream of calcium mobilization, i.e., activated ZAP70 and phospholipase C-1, in the disorganized NK cell immune synapse. Production of GM-CSF, but not IFN-, is decreased, while natural cytotoxicity of Wiskott-Aldrich syndrome-NK cells is maintained. Our results indicate that WASp independently regulates its dual functions, i.e., actin cytoskeletal remodeling and transcription in NK cells.

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