IgA Fc receptor I is a molecular switch that determines IgA activating or inhibitory functions.
IgA Fc receptor I, FcalphaRI or CD89, an ITAM-bearing receptor, has revealed unique genetic, structure and function features among immunoreceptors. While all genes encoding for the human Fc receptors are located in chromosome 1, the FcalphaRI gene has been found in a cluster in 19q13 that includes the killer inhibitory receptors (KIRs) and the leukocyteimmunoglobulin- like receptors (LIRs). FcalphaRI-IgA complexes display an original crystal structure and a 2:1 stoichiometry. Our results show that intrinsic signals elicited by FcalphaRI have outlined the particularity of this receptor, since it could function in two opposite ways: cell activation and inhibition of a heterologous FcR. Contrary to the dogma that receptor multimerization is necessary to ensure signaling, we demonstrated that monomeric targeting of FcalphaRI is sufficient to trigger a low-intensity signaling cascade that leads to cell desensitization by recruiting the tyrosine phosphatase SHP-1. By contrast, multimerization of FcalphaRI allows a high-intensity signaling pathway that leads to the recruitment of tyrosine kinase Syk and cell activation. Both types of signals require the FcRgamma-ITAM motif. This dual function is unique among ITAM-bearing FcR and led us to postulate that ITAM motifs could deliver an unexpected array of signaling intensity. These findings redefine FcalphaRI as a molecular switch of the immune system that mediates both pro- and anti-inflammatory functions of IgA.
Kanamaru
Yutaka
Y
INSERM U699, Bichat Campus, Paris, France.
Blank
Ulrich
U
Monteiro
Renato C
RC
D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000276:immunology; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism*; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism*
C045281:IgA receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc