title: The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation.
abstract: Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FcɛRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Restraint of intracellular signal transduction pathways that promote release of mast cell-derived pro-inflammatory mediators is necessary to dampen activation and restore homoeostasis. Here we show that the ligase Nedd4-2 and the adaptor Ndfip1 (Nedd4 family interacting protein 1) limit the intensity and duration of IgE-FcɛRI-induced positive signal transduction by ubiquitinating phosphorylated Syk, a tyrosine kinase that is indispensable for downstream FcɛRI signalosome activity. Importantly, loss of Nedd4-2 or Ndfip1 in mast cells results in exacerbated and prolonged IgE-mediated cutaneous anaphylaxis in vivo. Our findings reveal an important negative regulatory function for Nedd4-2 and Ndfip1 in IgE-dependent mast cell activity.
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors: Kwok Ho
authors: KH
authors: Yip
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors: Natasha
authors: N
authors: Kolesnikoff
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors: Nicholas
authors: N
authors: Hauschild
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors: Lisa
authors: L
authors: Biggs
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors: Angel F
authors: AF
authors: Lopez
authors: Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California 94305-5176, USA.
authors: Stephen J
authors: SJ
authors: Galli
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors: Sharad
authors: S
authors: Kumar
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.|OMNI-Biomarker Development, Genentech Inc., South San Francisco, California 94080, USA.
authors: Michele A
authors: MA
authors: Grimbaldeston
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000075702:Nedd4 Ubiquitin Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010323:Passive Cutaneous Anaphylaxis / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase / Q000276:immunology / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D017455:Receptors, IgE; D007073:Immunoglobulin E; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D000072377:Syk Kinase