Suppression of immunoglobulin E-mediated allergic responses by regulator of regulator of G protein signaling 13

Nature Immunology 9: 73-80 (2008)

Speaker：黃千晏                                                          Time：13:10~14:00, February 27, 2008

Commentator：王志堯 醫師                                       Place：Room 601

Abstract:

Type I hypersensitivity is an IgE-mediated immediate-type atopic allergy. When the allergens crosslink with IgE bound to Fc receptors (FcεRI) on the surface of tissue mast cells, the mast cells elicit allergic response through degranulation and the release of proinflammatory mediators. Some of the proinflammatory mediators, like sphingosine-1-phosphate, can further activate the G protein-coupled receptors (GPCRs) to amplify IgE-mediated mast cell activation (1). It was shown previously that the proteins of ‘regulator of G protein signaling’ (RGS) family inhibit the GPCRs-mediated signalings by its GTPase-accelerating protein (GAP) activity (2). In this study, the authors tested the role of R4 RGS proteins, a subfamily of RGS proteins with short peptide flanking the RGS domain, as potential regulators of allergic reaction. They found that among the R4 RGS protein, RGS13, was upregulated upon stimulation by IgE-antigen. The passive cutaneous and systemic anaphylaxis was enhanced in the Rgs13^-/- mice and this was due to the increased mast cell degranulation suggesting that RGS13 may suppress the IgE-mediated allergic responses. They then found that both the wild-type and GAP-inactive Tat-RGS13 inhibited the IgE-dependent mast cell degranulation in the Rgs13^-/- bone marrow mast cells suggesting that this property may be independent of the GAP activity. They further showed that RGS13 inhibited the activity of antigen-inducedphosphotidyl Phosphatidylinositol-3-OH kinase (PI(3)K), which plays an essential role in mast cell activation signaling pathway, by binding directly to the phosphorylated p85α subunit of PI(3)K. The authors also demonstrated that RGS13 inhibited the IgE-antigen triggered signaling by blocking the interaction of p85 of PI(3)K with the FcεRI-associated signaling complex containing Gab2 and Grb2 via its 51 N-terminal amino acids. In summary, the authors identified RGS13 as a negative regulator of IgE-mediated mast cell reactivity. This finding suggests that RGS13 may be used as a new treatment for patients with allergies.

References:

1. Gilfillan A.M. and Tkaczyk C. Integrated signaling pathways for mast-cell activation. Nat. Rev. Immunol. 6, 218-230 (2006)

2. Willars G. B. Mammalian RGS proteins: multifunctional regulators of cellular signalling. Semin. Cell Dev. Biol. 17, 363-376 (2006)