FCRLA is a resident endoplasmic reticulum protein that associates with intracellular Igs, IgM, IgG and IgA

Abstract

Fc receptor-like A (FCRLA) is an unusual member of the extended Fc receptor family. FCRLA has homology to receptors for the Fc portion of Ig (FCR) and to other FCRL proteins. However, unlike these other family representatives, which are typically transmembrane receptors with extracellular ligand-binding domains, FCRLA has no predicted transmembrane domain or N-linked glycosylation sites and is an intracellular protein. We show by confocal microscopy and biochemical assays that FCRLA is a soluble resident endoplasmic reticulum (ER) protein, but it does not possess the amino acid sequence KDEL as an ER retention motif in its C-terminus. Using a series of deletion mutants, we found that its ER retention is most likely mediated by the amino terminal partial Ig-like domain. We have identified ER-localized Ig as the FCRLA ligand. FCRLA is unique among the large family of Fc receptors, in that it is capable of associating with multiple Ig isotypes, IgM, IgG and IgA. Among hemopoietic cells, FCRLA expression is restricted to the B lineage and is most abundant in germinal center B lymphocytes. The studies reported here demonstrate that FCRLA is more broadly expressed among human B lineage cells than originally reported; it is found at significant levels in resting blood B cells and at varying levels in all B-cell subsets in tonsil.

Emerging Roles for the FCRL Family Members in Lymphocyte Biology and Disease

“…Davis, unpublished results). Human FCRLA is predominantly found in subsets of GC B cells, mainly the proliferating centroblasts, but is expressed at some level by all B cell subsets in the tonsil, with the notable exception of PCs where it is very low/absent, (Davis et al, 2002b, Facchetti et al, 2002, Mechetina et al, 2002, Masir et al, 2004) and in freshly isolated blood B cells (Santiago et al, 2011). In mice, FCRLA is broadly expressed among peripheral B cells, being highest in PCs, but is downregulated by GC B cells (Wilson et al, 2010, Reshetnikova et al, 2012).…”

“…Early studies using chimeric proteins artificially expressed on the cell surface failed to demonstrate interactions with Igs (Facchetti et al, 2002); however, immunoprecipitation of endogenous FCRLA disclosed its co-association with intracellular IgM, IgG, and IgA in cell lines as well as in primary B cells (Wilson et al, 2010, Santiago et al, 2011). The elevated expression of FCRLA in GC B cells, together with its ability to bind multiple isotypes of intracellular Ig, suggests a possible role for FCRLA in Ig retention during affinity maturation.…”

“…The elevated expression of FCRLA in GC B cells, together with its ability to bind multiple isotypes of intracellular Ig, suggests a possible role for FCRLA in Ig retention during affinity maturation. Indeed, FCRLA has been shown to preferentially associate in the ER with the secretory versus membrane form of IgM in the GC-like human B cell line Ramos (Santiago et al, 2011). Although FCRLB has even greater sequence identity with CD64, no evidence of Ig binding has been established for it yet and, like the Fcrla knockout mouse (Wilson et al, 2010), the Fcrlb knockout mouse had no discernible phenotype (Masuda et al, 2010).…”

Cutting Edge: Human FcRL4 and FcRL5 Are Receptors for IgA and IgG

“…Recently, FcRL6 has been reported to bind HLA-DR (24), and we and others have shown that intracellular FcRLA associates with multiple Ig isotypes within the lumen of the endoplasmic reticulum (25, 26). Given the homology of FcRL3-5 with FcγRI and the association between FcRLA and Igs, we decided to examine whether any of the FcRL proteins could bind Ig.…”

Opportunities to Exploit Non-Neutralizing HIV-Specific Antibody Activity

“…The intracellular TRIM21 receptor is involved in proteasomal targeting of IgG opsonized virus(93). Other IgG binding proteins, such as as Fcγ binding protein (FcγBP), which associates with mucus at epithelial barriers(93, 94), and FcR-like (FcRL) receptors 4,5, and A(95, 96) are all known to bind IgG, but remain poorly characterized. The role these and other IgG receptors may play in determining the disposition of Ab-opsonized virus or infected cells in HIV remains to be determined.…”