Complement Receptor of Immunoglobulin Family (CRIg)

Complement receptor of immunoglobulin family (CRIg), also known as V-set and immunoglobulin domain-containing protein 4 or Z39Ig, is a member of B7 family proteins encoded by VSIG4 gene located on the human X chromosome. CRIg was later identified as a novel complement receptor expressed by macrophages, which binds to C3b, iC3b, and C3c molecules. CRIg is a type 1 transmembrane protein composed of 399 amino acids, presenting in two alternatively spliced forms, CRIg(L) and CRIg(S). Both two human CRIg isoforms contain an N-terminal IgV-type immunoglobulin domain, and CRIg(L) contains an additional IgC-type immunoglobulin domain at the membrane-proximal end. Mouse CRIg lacks the IgC-type immunoglobulin domain, resembling the CRIg(S) form. The IgV-type immunoglobulin domain is significant for the binding of CRIg to complement fragments and CRIg-related phagocytosis.

CRIg specifically recognizes the beta chain of C3b and iC3b that are deposited on particle surfaces, playing a critical role in C3-mediated opsonization. The extracellular domain of CRIg was found to block the activation of complement alternative pathway, of which inhibitory mechanism is unclear. Moreover, CRIg also has been indicated to be implicated in multiple functions, including the clearance of the intracellular pathogens by Kupffer cells, the regulation of T-cell proliferation, and adaptive immune responses. The IgV domain of CRIg fusion with other functional proteins has been shown to have relieved effects on diseases in animal models, such as traumatic brain injury, arthritis, uveitis, and so forth.

Fig. 1 The role of CRIg on tumor cells.¹

Reference

1. Golay, Josée, and Ronald P. Taylor. "The role of complement in the mechanism of action of therapeutic anti-cancer mAbs." Antibodies 9.4 (2020): 58.