Impaired FcϵRI stability, signaling, and effector functions in murine mast cells lacking glycosylphosphatidylinositol-anchored proteins

Author:

Hazenbos Wouter L. W.1,Wu Ping1,Eastham-Anderson Jeffrey2,Kinoshita Taroh3,Brown Eric J.1

Affiliation:

1. Program of Host-Pathogen Interactions, University of California, San Francisco, CA;

2. Deptartment of Pathology, Genentech Inc, South San Francisco, CA; and

3. Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Abstract

AbstractA key event and potential therapeutic target in allergic and asthmatic diseases is signaling by the IgE receptor FcϵRI, which depends on its interactions with Src family kinases (SFK). Here we tested the hypothesis that glycosylphosphatidylinositiol-anchored proteins (GPI-AP) are involved in FcϵRI signaling, based on previous observations that GPI-AP colocalize with and mediate activation of SFK. We generated mice with a hematopoietic cell-specific GPI-AP deficiency by targeted disruption of the GPI biosynthesis gene PigA. In these mice, IgE-mediated passive cutaneous anaphylaxis was largely abolished. PigA-deficient mast cells cultured from these mice showed impaired degranulation in response to stimulation with IgE and antigen in vitro, despite normal IgE binding and antigen-induced FcϵRI aggregation. On stimulation of these cells with IgE and antigen, coprecipitation of the FcϵRI α-chain with the γ-chain and β-chain was markedly reduced. As a result, IgE/antigen–induced FcϵRI-Lyn association and γ-chain tyrosine phosphorylation were both impaired in PigA-deficient cells. These data provide genetic evidence for an unanticipated key role of GPI-AP in FcϵRI interchain interactions and early FcϵRI signaling events, necessary for antigen-induced mast cell degranulation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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