ULBP3 Gene – Structure, Function, and Clinical Significance

ULBP3 (UL16 binding protein 3) is a member of the ULBP/RAET1 family of glycoproteins that serve as ligands for the NKG2D receptor expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells. The gene is located on chromosome 6q25.1 and encodes a cell surface protein with alpha-helical and MHC class I-like domains. ULBP3 is typically absent or low on normal cells but is upregulated under stress conditions such as viral infection, DNA damage, or oncogenic transformation. Binding of ULBP3 to NKG2D triggers cytotoxic immune responses, making it a critical component of innate and adaptive immune surveillance. Alternative splicing produces multiple transcript variants.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• NKG2D signaling in NK cells (Reactome: R-HSA-199043)

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

• Natural killer cell mediated cytotoxicity (KEGG: hsa04650)

ULBP3 is a 221-amino-acid type I transmembrane glycoprotein with an extracellular domain containing alpha-1 and alpha-2 helices similar to MHC class I molecules, but it does not bind β2-microglobulin or present peptides. The protein is anchored via a glycosylphosphatidylinositol (GPI) linkage in some isoforms. It interacts specifically with the NKG2D receptor (KLRK1) on immune effector cells, leading to activation of cytotoxicity and cytokine production. ULBP3 is encoded by the RAET1N gene and is also known as ALCAN-β. Post-translational modifications include N-glycosylation and GPI-anchor addition.