UL16-binding protein family (ULBP)

The UL16-binding protein (ULBP) family, also known as the RAET1 family, comprises six human glycoproteins (ULBP1-6) that function as ligands for the NKG2D activating receptor found on natural killer (NK) cells and various T cell subsets [1][2]. These proteins are structurally homologous to MHC class I molecules but do not present peptides or associate with beta-2 microglobulin [3]. Under normal physiological conditions, ULBPs are minimally expressed on healthy tissues; however, they are rapidly upregulated in response to cellular stressors such as DNA damage, viral infection, or oncogenic transformation [4][5]. This "induced-self" expression marks compromised cells for elimination by the immune system, making the ULBP family a high-priority target for cancer immunotherapies, including CAR-T cells and bispecific engagers [6][7]. Clinical candidates like CYAD-01 utilize the NKG2D receptor to target the broad expression of ULBPs across multiple hematological and solid malignancies [8]. A significant challenge in targeting this family is the proteolytic shedding of ULBPs from the cell surface, which creates soluble decoys that can desensitize NKG2D receptors and facilitate tumor immune evasion [9].

Other names

RAET1 proteinsRetinoic acid early transcript 1 familyNKG2D ligandsUL16-binding proteinsULBP1-6

Activation of the NKG2D receptor on natural killer (NK) cells and cytotoxic T cells to induce targeted lysis of cells expressing ULBP ligands.