The Wiskott-Aldrich syndrome protein regulates nuclear translocation of NFAT2 and NF-kappa B (RelA) independently of its role in filamentous actin polymerization and actin cytoskeletal rearrangement.
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-kappaB (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-gamma1, in the disorganized NK cell immune synapse. Production of GM-CSF, but not IFN-gamma, 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.
Huang
Winifred
W
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute for Cancer Research, New York, NY 10021, USA.
Ochs
Hans D
HD
Dupont
Bo
B
Vyas
Yatin M
YM
D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism*; D002999:Clone Cells; D003599:Cytoskeleton / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000502:physiology; D021962:Membrane Microdomains / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors; D055627:Natural Cytotoxicity Triggering Receptor 1; D009687:Nuclear Proteins / Q000378:metabolism*; D051966:Phospholipase C gamma; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein
D000199:Actins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C112260:NCR1 protein, human; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D055627:Natural Cytotoxicity Triggering Receptor 1; D009687:Nuclear Proteins; D011506:Proteins; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D014157:Transcription Factors; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010738:Type C Phospholipases; D051966:Phospholipase C gamma