A Truncated Splice-Variant of the Fc[epsilon]RI[beta] Receptor Subunit Is Critical for Microtubule Formation and Degranulation in Mast Cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2013-05, Vol.38 (5), p.906
• Main Authors: Cruse, Glenn, Beaven, Michael A, Ashmole, Ian, Bradding, Peter, Gilfillan, Alasdair M, Metcalfe, Dean D
• Format: Article
• Language: English
• Subjects: Allergies; Asthma; Phosphorylation; Protein expression; Proteins
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.04.007

Human linkage analyses have implicated theMS4A2-containing gene locus (encoding Fc[straight epsilon]RIβ) as a candidate for allergy susceptibility. We have identified a truncation of Fc[straight epsilon]RIβ (t-Fc[straight epsilon]RIβ) 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-Fc[straight epsilon]RIβ 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-Fc[straight epsilon]RIβ in the presence of Ca2+could be critical for t-Fc[straight epsilon]RIβ function. In addition, gene targeting of t-Fc[straight epsilon]RIβ attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+signals. Therefore, t-Fc[straight epsilon]RIβ mediates Ca2+-dependent microtubule formation, which promotes degranulation and cytokine release. Because t-Fc[straight epsilon]RIβ has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation.