title: A truncated splice-variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells.
abstract: Human linkage analyses have implicated the MS4A2-containing gene locus (encoding FcεRIβ) as a candidate for allergy susceptibility. We have identified a truncation of FcεRIβ (t-FcεRIβ) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-FcεRIβ is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-FcεRIβ in the presence of Ca2+ could be critical for t-FcεRIβ function. In addition, gene targeting of t-FcεRIβ attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-FcεRIβ mediates Ca2+ -dependent microtubule formation, which promotes degranulation and cytokine release. Because t-FcεRIβ has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation.
authors: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. glenncruse@hotmail.com
authors: Glenn
authors: G
authors: Cruse
authors: Michael A
authors: MA
authors: Beaven
authors: Ian
authors: I
authors: Ashmole
authors: Peter
authors: P
authors: Bradding
authors: Alasdair M
authors: AM
authors: Gilfillan
authors: Dean D
authors: DD
authors: Metcalfe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D016209:Interleukin-8 / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000276:immunology; D020033:Protein Isoforms / Q000276:immunology; D034622:RNA Interference; D012326:RNA Splicing; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002148:Calmodulin-Binding Proteins; C490895:GAB2 protein, human; D016209:Interleukin-8; C502447:MS4A2 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D007073:Immunoglobulin E; D015230:Prostaglandin D2; D002118:Calcium
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