UL16-binding protein 4 (ULBP4)

UL16-binding protein 4 (ULBP4), also known as RAET1E, is a member of the RAET1 family of MHC class I-related proteins that serves as a stress-induced ligand for the activating receptor NKG2D (KLRK1) [3, 7]. Unlike many other ULBPs that are glycosylphosphatidylinositol (GPI)-anchored, ULBP4 is a type I transmembrane protein expressed predominantly in the skin, trachea, and certain tumors [4, 10]. Its primary biological function is to alert the immune system to cellular distress, malignancy, or viral infection, thereby triggering natural killer (NK) cell and T cell-mediated cytotoxicity [11, 13]. In oncology, ULBP4 is frequently upregulated in various cancers, including colorectal, ovarian, and liver carcinomas, making it a key component for immune recognition [14, 15]. However, its therapeutic utility is complicated by tumor escape mechanisms, such as the proteolytic shedding of ULBP4 into a soluble form that acts as a decoy and downregulates the NKG2D receptor [8, 11]. Beyond cancer, ULBP4 has been identified as a factor in the neuroinflammatory pathology of multiple sclerosis, where it is upregulated by astrocytes and enhances proinflammatory CD8+ T cell activities [6, 8]. Due to its restricted expression in healthy tissues and high expression in many cancers, it is an active target for development in adoptive cell therapies, particularly NKG2D-based chimeric antigen receptor (CAR) T cells [12, 16].

Other names

Retinoic acid early transcript 1ERAET1EN2DL-4LETALLymphocyte effector toxicity activation ligandNKG2DL4RAE-1-like transcript 4

Binds and activates the NKG2D (KLRK1) receptor on natural killer cells and CD8+ T cells to trigger cytotoxic activity and cytokine production.