VSIG4 Gene - Structure, Function, and Clinical Significance

VSIG4 (V-set and immunoglobulin domain containing 4), also known as CRIg (complement receptor of the immunoglobulin superfamily), is a type I transmembrane protein encoded by the VSIG4 gene on chromosome Xq12. It functions as a receptor for complement components C3b and iC3b, mediating phagocytosis of opsonized particles. Additionally, VSIG4 acts as an immune checkpoint molecule by inhibiting T-cell proliferation and activation. It is predominantly expressed in macrophages, particularly in the liver (Kupffer cells), and plays roles in innate immunity, tissue homeostasis, and cancer immune evasion.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Complement cascade (Reactome: R-HSA-166658)

• Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (Reactome: R-HSA-198933)

• Phagocytosis (Reactome: R-HSA-2029480)

VSIG4 (CRIg) is a 399-amino acid transmembrane protein with a signal peptide, an N-terminal V-set immunoglobulin domain, a C2-set Ig domain, a transmembrane region, and a short cytoplasmic tail. It binds complement fragments C3b and iC3b, mediating phagocytosis of opsonized targets. On macrophages, VSIG4 also delivers a co-inhibitory signal to T cells, suppressing proliferation and cytokine production. The protein is highly expressed on Kupffer cells in the liver and on tissue-resident macrophages, contributing to immune homeostasis and pathogen clearance. In cancer, VSIG4 upregulation on tumor-associated macrophages is associated with poor prognosis and immune evasion.