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The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation

Author

Listed:
  • Kwok Ho Yip

    (Centre for Cancer Biology, University of South Australia and SA Pathology)

  • Natasha Kolesnikoff

    (Centre for Cancer Biology, University of South Australia and SA Pathology)

  • Nicholas Hauschild

    (Centre for Cancer Biology, University of South Australia and SA Pathology)

  • Lisa Biggs

    (Centre for Cancer Biology, University of South Australia and SA Pathology)

  • Angel F. Lopez

    (Centre for Cancer Biology, University of South Australia and SA Pathology
    School of Medicine, University of Adelaide)

  • Stephen J. Galli

    (and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine)

  • Sharad Kumar

    (Centre for Cancer Biology, University of South Australia and SA Pathology
    School of Medicine, University of Adelaide)

  • Michele A. Grimbaldeston

    (Centre for Cancer Biology, University of South Australia and SA Pathology
    School of Medicine, University of Adelaide
    OMNI-Biomarker Development, Genentech Inc.)

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.

Suggested Citation

  • Kwok Ho Yip & Natasha Kolesnikoff & Nicholas Hauschild & Lisa Biggs & Angel F. Lopez & Stephen J. Galli & Sharad Kumar & Michele A. Grimbaldeston, 2016. "The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13198
    DOI: 10.1038/ncomms13198
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