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.
Highlights
Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FceRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma
We have found that mast cells express Nedd[] and importantly, loss of Nedd[] in foetal liver-derived mast cells (FLMCs) or bone marrow-derived cultured mast cells (BMCMCs) results in heightened and sustained pro-inflammatory mediator release by mast cells in vitro, and in prolonged IgE-mediated passive cutaneous anaphylaxis reactions in three different types of mast cell-deficient mice engrafted with Nedd[] À / À mast cells
B6-mouse mast cells, derived from cultured bone marrow (BMCMCs) or embryonic (E18.5) foetal liver cells[26] (FLMCs), express this ubiquitin ligase and that this is not true of mast cells derived from C57BL/6-Nedd[] À / À mice which exhibit a complete loss of Nedd[] expression[27] (Supplementary Fig. 1a)
Summary
Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FceRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Syk kinase is activated in a process that is thought to involve Lyn[12] and Fgr[9], and is recruited to distinct binding sites in the g subunit ITAM where it serves to amplify signal transduction. Key to this function and to its essential role in the calcium response, degranulation and cytokine production following FceRI engagement[13], is the capacity of cytosolic Syk to interact with multiple signalling proteins. E3 ubiquitin ligases are responsible for the attachment of ubiquitin chains to select target proteins, a modification that can prompt endocytosis of cell surface receptors and initiate proteasomal or lysosomal degradation of signalling proteins[17,18]
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