ULBP5 (UL16-binding protein 5) (ULBP5)

ULBP5, also known as RAET1G or UL16-binding protein 5, is a stress-inducible ligand for the activating immunoreceptor NKG2D, expressed on NK cells, γδ T cells, and CD8+ T cells. It features an MHC class I-like ectodomain that binds NKG2D, triggering cytotoxic responses against virally infected or transformed cells, unlike GPI-anchored ULBPs 1-3, ULBP5 has transmembrane and cytoplasmic domains. ULBP5 exists in two isoforms: full-length RAET1G1 with unique transmembrane and cytoplasmic regions, and RAET1G2, which is secreted and may contribute to immune evasion by downregulating NKG2D surface expression. It is upregulated in epithelial cancers, including breast cancer, and primary tumors, promoting anti-tumor immunosurveillance via NKG2D-mediated cytotoxicity. However, RAET1G shows weaker NKG2D binding affinity than related ligands like ULBP2 due to an amino acid substitution in its α2 domain, resulting in less efficient NK cell degranulation and receptor downregulation. Soluble forms of ULBP5 isoforms can shed from cells, potentially impairing NKG2D function and aiding tumor escape. Overall, ULBP5 contributes to innate immunity but its variable expression and isoforms highlight diversity in NKG2D ligand biology for pathogen and cancer surveillance.

Other names

RAET1GULBP-5NKG2D ligand 5