UL16-binding protein 4 (retinoic acid early transcript 1E) (ULBP4 (RAET1E))

UL16-binding protein 4 is a human nonclassical MHC class I–related, GPI-anchored cell-surface glycoprotein encoded by RAET1E on chromosome 6q24.2–q25.3 and is a member of the ULBP/RAET1 family of NKG2D ligands. ULBP4 serves as an activating ligand for the NK and T-cell receptor NKG2D (KLRK1), promoting NK-cell cytotoxicity and cytokine production; uniquely, it can also engage the Vγ9Vδ2 T-cell receptor to activate γδ T cells. ULBP4 expression is stress induced, found on certain normal tissues (notably skin) and upregulated on multiple tumor types and some virally infected cells (e.g., EBV). Within the ULBP family, ULBP4 is “peculiar” due to distinct processing, alternative splicing affecting its cytoplasmic tail, and population variants influencing glycosylation sites, which can alter expression and detection. Unlike some other ULBPs, ULBP4 is reported not to interact with the HCMV immunoevasin UL16, a feature relevant to viral immune evasion pathways. Collectively, these properties position ULBP4 as a therapeutically relevant immune ligand in oncology and infectious disease immunotherapy.

Other names

Retinoic acid early transcript 1E (RAET1E)NKG2D ligand 4 (NKG2DL4)RAET1E2 (soluble isoform)LETAL (lymphocyte effector toxicity activation ligand)RL-4; RAE-1-like transcript 4KLRK1 ligand; N2DL4Note: ULBP4 does not bind HCMV UL16 (unlike some other ULBPs)

Agents that enhance ULBP4 expression on tumor cells to increase NKG2D-mediated cytotoxicity (inferred from NKG2D–ULBP biology). Biologics or cell therapies leveraging NKG2D recognition of ULBP4 to trigger NK/γδ T-cell killing (e.g., NKG2D-based engagement) (family/axis-based mechanism). Decoy/soluble ligands or antibodies could modulate NKG2D signaling; RAET1E2 soluble isoform can inhibit NKG2D-mediated NK cytotoxicity.