UL16-binding protein 1–6 (ULBP1–6)

UL16-binding protein 1–6 (ULBP1–6) is a family of human cell-surface glycoproteins that act as ligands for the NKG2D (KLRK1) activating receptor, which is expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells (Frontiers in Immunology, 2017). These proteins, also known as Retinoic Acid Early Transcript 1 (RAET1) molecules, are structurally related to MHC class I molecules but lack the α3 domain and do not present peptides (UniProt Q9BZM6; Wikipedia). The family includes both GPI-anchored members (ULBP1, 2, 3, and 6) and transmembrane members (ULBP4 and 5) (NIH, 2024). While typically absent in healthy tissues, ULBPs are highly induced by cellular stressors such as viral infection, DNA damage, and malignant transformation, serving as signals for immune-mediated elimination (Frontiers in Immunology, 2017). This makes them critical targets for cancer immunotherapy, where they are leveraged by NKG2D-based chimeric antigen receptor (CAR) T and NK cell therapies, such as CYAD-01 and CYAD-02, to recognize and eliminate a wide variety of hematological and solid tumors (Cusabio; Celyad Oncology). However, tumors often employ evasion mechanisms, including the shedding of ULBPs into soluble forms that act as decoys or the use of viral proteins (e.g., HCMV UL16) to sequester the ligands intracellularly, thereby avoiding immune detection (Frontiers in Immunology, 2011; NIH, 2008).

Other names

RAET1 familyNKG2D ligandsNKG2DLRetinoic acid early transcript 1 proteinsULBP1 (RAET1I)ULBP2 (RAET1H)ULBP3 (RAET1N)ULBP4 (RAET1E)ULBP5 (RAET1G)ULBP6 (RAET1L)N2DL-1N2DL-2N2DL-3N2DL-4

Activation of NKG2D-mediated cytotoxicity through direct binding of therapeutic receptors (e.g., CARs) or antibodies to surface-expressed ULBP ligands on target cells.