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

Kwok Ho Yip, Natasha Kolesnikoff, Nicholas Hauschild, Lisa Biggs, Angel F. Lopez, Stephen J. Galli, Sharad Kumar and Michele A. Grimbaldeston ()
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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
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
Michele A. Grimbaldeston: Centre for Cancer Biology, University of South Australia and SA Pathology

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13198

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