FCRL5

Official Full Name

Fc receptor like 5

Organism

Homo sapiens

GeneID

83416

Background

This gene encodes a member of the immunoglobulin receptor superfamily and the Fc-receptor like family. This gene and several other Fc receptor-like gene members are clustered on the long arm of chromosome 1. The encoded protein is a single-pass type I membrane protein and contains 8 immunoglobulin-like C2-type domains. This gene is implicated in B cell development and lymphomagenesis. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Sep 2010]

Synonyms

CD307; FCRH5; IRTA2; BXMAS1; CD307e; PRO820;

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Detailed Information

The FCRL5 gene, located on human chromosome 1q21–1q22, is an important member of the Fc receptor-like (FCRL) family within the immunoglobulin superfamily. This gene cluster includes multiple FCRL genes, reflecting an evolutionary history likely shaped by gene duplication events. FCRL5 encodes a type I transmembrane protein whose extracellular region contains up to eight immunoglobulin-like C2-type domains, suggesting its involvement in recognizing diverse ligands and mediating complex intercellular interactions. Unlike classical Fc receptors, FCRL5 lacks canonical motifs for high-affinity binding to immunoglobulin constant regions, classifying it as an "orphan receptor", and its specific endogenous ligands remain under investigation. Expression of FCRL5 is highly lineage-specific, largely restricted to B lymphocytes at different developmental stages, from early B cell precursors to mature B cell subsets, particularly marginal zone B cells and plasma cells, with dynamic expression levels. Alternative splicing produces multiple transcript variants encoding distinct protein isoforms, adding further complexity and diversity to its functional regulation.

Biological Significance

FCRL5 functions as a dual regulator of B cell receptor (BCR) signaling, integrating microenvironmental cues and co-receptor engagement to fine-tune B cell responses to antigens. In the absence of co-stimulatory signals, its intracellular domain contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs). When recruited near the BCR signaling complex, ITIMs can be phosphorylated by Src-family kinases, leading to recruitment and activation of phosphatases such as SHP-1, which dephosphorylate key BCR signaling components, thereby dampening B cell activation. Conversely, when B cells receive co-stimulation through complement receptor 2 (CR2), FCRL5 switches function: it cooperates with CR2 to produce calcium responses stronger than BCR or BCR+CR2 stimulation alone, promoting full B cell activation, proliferation, immunoglobulin class switching, and plasma cell differentiation. This makes FCRL5 a "molecular switch", acting as a brake or accelerator depending on the immune context. Such precise modulation is critical for maintaining humoral immune balance, preventing inappropriate B cell activation under basal conditions while amplifying protective antibody responses when necessary.

Figure 1. Regulation of BCR signaling and B-cell function by FCRLs. (Rostamzadeh D, et al., 2018)

Clinical Relevance

Clinically, FCRL5 has significance as a biomarker and potential immunotherapy target in B cell malignancies. Aberrant high expression is observed in multiple B cell lymphomas and leukemias, particularly hairy cell leukemia and certain subtypes of chronic lymphocytic leukemia, making it a valuable tool for tumor subclassification and minimal residual disease monitoring. Its surface-specific expression and role in promoting B cell survival and proliferation have spurred the development of antibody-drug conjugates (ADCs) and bispecific antibodies targeting FCRL5, currently in preclinical or early clinical development. These strategies aim to selectively deliver cytotoxic agents or T cell effector activity to FCRL5-expressing malignant B cells, achieving precision targeting while minimizing off-target effects.

In autoimmune diseases, although research is preliminary, dysregulation of FCRL5 signaling may contribute to pathologic autoantibody production, suggesting that modulating its activity could help restore B cell tolerance. Challenges remain, including identifying endogenous ligands, clarifying whether FCRL5 primarily mediates inhibitory or activating signals under different pathological states, and ensuring that targeted therapies do not disrupt normal B cell subsets critical for immune function. Overall, FCRL5 is a functionally complex, B cell-specific regulatory molecule, evolving from a subject of basic immunology research to a promising novel target in tumor immunotherapy.

References

Li FJ, Won WJ, Becker EJ Jr, et al. Emerging roles for the FCRL family members in lymphocyte biology and disease. Curr Top Microbiol Immunol. 2014;382:29–50.
Wilson TJ, Fuchs A, Colonna M. Cutting edge: human FcRL4 and FcRL5 are receptors for IgA and IgG. J Immunol. 2012;188(10):4741–4745.
Rostamzadeh D, Kazemi T, Amirghofran Z, et al. Update on Fc receptor-like (FCRL) family: new immunoregulatory players in health and diseases. Expert Opin Ther Targets. 2018 Jun;22(6):487-502.

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