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

Nature Immunology volume 9, pages 73–80 (2008)Cite this article

Abstract

Mast cells elicit allergic responses through degranulation and release of proinflammatory mediators after antigen crosslinking of the immunoglobulin E receptor FcεRI. Proteins of the 'regulator of G protein signaling' (RGS) family negatively control signaling mediated by G protein–coupled receptors through GTPase-accelerating protein activity. Here we show that RGS13 inhibited allergic responses by physically interacting with the regulatory p85α subunit of phosphatidylinositol-3-OH kinase in mast cells and disrupting its association with an FcεRI-activated scaffolding complex. Rgs13−/− mice had enhanced immunoglobulin E–mediated mast cell degranulation and anaphylaxis. Thus, RGS13 inhibits the assembly of immune receptor–induced signalosomes in mast cells. Abnormal RGS13 expression or function may contribute to disorders of amplified mast cell activity, such as idiopathic anaphylaxis.

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Figure 1: Expression of RGS13 by BMMCs.
Figure 2: RGS13 inhibits IgE-dependent mast cell degranulation independently of GAP activity.
Figure 3: Enhanced passive cutaneous anaphylaxis in Rgs13−/− mice.
Figure 4: RGS13 interacts with the regulatory p85α subunit of PI(3)K.
Figure 5: Rgs13−/− mast cells have enhanced antigen-elicited PI(3)K activity and 'downstream' signaling events.
Figure 6: RGS13 expression in wild-type BMMCs inhibits antigen-induced Ca2+ flux and Akt activation.
Figure 7: Mechanism of the inhibition of antigen-induced PI(3)K activity by RGS13 in mast cells.

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Acknowledgements

We thank S. Dowdy (University of California, San Diego, School of Medicine) and J.S. Gutkind (National Institute of Dental and Craniofacial Research, National Institutes of Health) for plasmids; S. Iwaki and A. Gilfillan for reagents, protocols, discussions and critical review of the manuscript; J. Kehrl (National Institute of Allergy and Infectious Diseases, National Institutes of Health) for anti-RGS13 and D. Metcalfe for support.

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  1. Sudhir Rao & Karl H Nocka

    Present address: Present addresses: Merck Research Laboratories, Boston, Massachusetts 02115, USA (S.R.) and Wyeth Research, Cambridge, Massachusetts 02140, USA (K.H.N).,

  2. Geetanjali Bansal and Zhihui Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Geetanjali Bansal, Zhihui Xie & Kirk M Druey

  2. UCB Pharma, Cambridge, 02139, Massachusetts, USA

    Sudhir Rao & Karl H Nocka

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Contributions

G.B., Z.X. and K.D. did experiments, analyzed data and wrote the paper; and S.R. and K.H.N. did experiments and analyzed data.

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Correspondence to Kirk M Druey.

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K.H.N. and S.R. were employees of USB Pharma when the microarray data were collected.

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Bansal, G., Xie, Z., Rao, S. et al. Suppression of immunoglobulin E–mediated allergic responses by regulator of G protein signaling 13. Nat Immunol 9, 73–80 (2008). https://doi.org/10.1038/ni1533

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