FCRLA is an intracellular FcR-related protein that binds IgM, IgG and IgA isotypes in B cells (45.11)

Abstract

Abstract Fc-receptor-like A (FCRLA) is a novel member of the extended Fc receptor (FcR) family. Unlike the classical FcRs and Fc receptor-like (FCRL) molecules, which are typically transmembrane receptors with extracellular ligand binding domains, FCRLA has no predicted transmembrane domain or N-linked glycosylation sites and is positioned intracellularly. We show by confocal microscopy and biochemical assays that FCRLA is a soluble, resident ER protein; however, it lacks a characteristic KDEL retention sequence at its C-terminus. Using a series of deletion mutants, we found that its ER retention is most likely mediated by the amino terminal domain. We have also recently identified ER localized immunoglobulin as an FCRLA ligand. These results indicate that FCRLA is unique among the large FcR family in that can associate with multiple immunoglobulin isotypes, including IgM, IgG, and IgA. To better understand the role of this protein in human disease, B cell chronic lymphocytic leukemia (CLL) samples were assayed for FCRLA expression by flow cytometry. Interestingly, the receptor was more highly expressed by the indolent form of CLL, which is distinguished by somatically hypermutated heavy chain variable region genes, than by the aggressive high-risk form, which features more germline B cell receptor characteristics. These results indicate that FCRLA may thus be a useful diagnostic marker for CLL.