Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Unique Role of the FcRI (CD64) Cytoplasmic Domain in Mediating Phosphorylation Dependent Lipid Raft Localization.

Gibson3,  Andrew G., Li3,  Xinrui, Edberg2,  Jeffrey C., Kimberly1,  Robert P.

Univ Alabama at Birmingham, Birmingham, AL
University of Alabama at Birmingham, Birmingham, AL
University of Alabama at Birmingham

The overproduction of type I Interferon and systemic inflammation in lupus patients correlates with increased monocyte surface expression of FcgRI (CD64), a receptor for both IgG and C reactive protein (CRP). Despite signaling through the common ITAM motifs shared by other activating FcgRs, FcgRI mediates distinct cellular programs such as the cell surface cleavage and release of functional soluble BLyS/BAFF upon FcgRI cross-linking by CRP or IgG. To explore the mechanism(s) of additional unique FcgRI properties, we probed the critical contributions of the distinct cytoplasmic tail (CY) of FcgRI a-chain in inducing receptor functions. Unlike other FcR, the FcgRI CY domain contains serine residues that are phosphorylated by CK2 in vitro, and the cytoplasmic domain of FcgRI is constitutively phosphorylated in resting cells. As a consequence, the binding of protein 4.1G, a novel partner associated with FcgRI a-chain CY but not with other FcR CY, is greatly promoted when FcgRI CY is phosphorylated. Since other members of the protein 4.1G family (the Four.1 protein, Ezrin, Radixin, Moesin (FERM) family) have been shown to facilitate lipid raft association of TCR and BCR to promote formation of immunological synapses, we hypothesized that serine phosphorylation of FcgRI CY with increased association with protein 4.1G would further promote the ability of FcgRI to associate with lipid rafts. Consistent with earlier reports, we observed that FcgRI constitutively resides in lipid rafts in macrophages transfected with human FcgRI. However, in cells transfected with a mutated form of human FcgRI lacking the ser-based CK2 phosphorylation site(s), FcgRI was distributed predominately outside of lipid microdomains, indicating that phosphorylation of FcgRI CY is required for lipid raft colocalization. These results are consistent with a role for protein 4.1G in tethering FcgRI within lipid rafts. The phosphotyrosine-based g-chain signaling plus the phosphoserine-based a-chain signaling form a unique FcgRI signaling pathway. These results provide additional insights into the unique signaling potential of FcgRI that can explain the previously documented unique functional potential of FcgRI. Further mechanistic studies into the regulation of FcgRI function will allow a determination of the importance of increased expression of this receptor in patients with lupus.

To cite this abstract, please use the following information:
Gibson, Andrew G., Li, Xinrui, Edberg, Jeffrey C., Kimberly, Robert P.; Unique Role of the FcRI (CD64) Cytoplasmic Domain in Mediating Phosphorylation Dependent Lipid Raft Localization. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :868
DOI: 10.1002/art.28636

Abstract Supplement

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