ULBP1

Official Full Name

UL16 binding protein 1

Organism

Homo sapiens

GeneID

80329

Background

The protein encoded by this gene is a ligand of natural killer group 2, member D (NKG2D), an immune system-activating receptor on NK cells and T-cells. Binding of the encoded ligand to NKG2D leads to activation of several signal transduction pathways, including those of JAK2, STAT5, ERK and PI3K kinase/Akt. Also, in cytomegalovirus-infected cells, this ligand binds the UL16 glycoprotein and is prevented from activating the immune system. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

Synonyms

N2DL-1; RAET1I; NKG2DL1;

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Detailed Information

The ULBP1 gene, officially named UL16-binding protein 1, belongs to the RAET1 gene family and is located on human chromosome 6q25.1. ULBP1 encodes a cell surface ligand that serves as a critical recognition molecule for the natural killer (NK) group 2 member D (NKG2D) receptor. Structurally, ULBP1 exhibits weak similarity to classical MHC class I molecules, characterized by an α1/α2-like fold; however, it does not associate with β2-microglobulin and lacks a transmembrane domain. Instead, ULBP1 is anchored to the cell membrane via a C-terminal glycosylphosphatidylinositol (GPI) linkage, which confers higher lateral mobility and allows for potential enzymatic shedding. ULBP1 is one of several ligands for NKG2D, a receptor family that also includes ULBP2–6 and MICA/B. This multi-ligand/single-receptor system enables cells to transmit diverse "stress signals" to activate the NKG2D pathway. In normal tissues, ULBP1 expression is tightly restricted but is significantly upregulated under cellular stress, such as viral infection, DNA damage, malignant transformation, or heat shock.

Biological Significance

ULBP1 functions as a "danger signal" or stress-induced ligand, playing a central role in innate immunity and γδ T cell–mediated immune surveillance. When cells become stressed due to infection or transformation, ULBP1 is upregulated and displayed on the cell surface, effectively serving as a "flag" recognized by the activating receptor NKG2D, which is expressed on NK cells, CD8+ αβ T cells, and γδ T cells. Engagement of ULBP1 with NKG2D provides potent activation signals, triggering cytotoxic granule release and cytokine production, leading to the elimination of stressed or abnormal cells. The ULBP1–NKG2D axis thus represents a critical first line of immune surveillance, linking intracellular stress to the activation of the immune system.

Figure 1. Human NKG2D receptor and its cognate ligands. (Han J, et al., 2025)

Pathogens, particularly members of the herpesvirus family such as human cytomegalovirus (HCMV), have evolved mechanisms to evade this system. The viral UL16 glycoprotein binds specifically to ULBP1 (and other ULBPs) and retains them in the endoplasmic reticulum or Golgi, preventing surface expression. This effectively masks the "danger signal," allowing infected cells to escape NK cell–mediated recognition and killing. In tumors, although ULBP1 is often upregulated, cancer cells may shed soluble ULBP1 to downregulate NKG2D on lymphocytes or employ other immunosuppressive strategies, illustrating the complexity of tumor immune editing.

Clinical Relevance

ULBP1 is a promising target and biomarker in cancer immunotherapy. Its restricted expression in normal tissues and high, stress-induced expression in malignant cells make the ULBP1–NKG2D axis an attractive therapeutic target. Strategies include NKG2D-based chimeric antigen receptor (CAR) engineered immune cells, where the extracellular domain of NKG2D is expressed in NK cells or T cells to enable recognition of multiple ULBP1-positive tumors. Another approach involves bispecific antibodies targeting ULBP1 and CD3 to recruit T cells directly to ULBP1-expressing tumor cells, eliciting potent cytotoxic responses.

ULBP1 expression also has prognostic and diagnostic significance. In cancers such as multiple myeloma, nasopharyngeal carcinoma, and certain acute leukemias, high surface ULBP1 correlates with favorable prognosis or better treatment response, likely reflecting increased immune recognition. Measurement of soluble ULBP1 in patient serum may serve as a noninvasive biomarker for monitoring disease progression or therapy response. In infectious diseases, particularly HCMV infection, understanding viral UL16-mediated interference with ULBP1 informs antiviral strategies. Challenges remain in overcoming tumor microenvironment suppression of NKG2D signaling and managing potential "on-target, off-tumor" toxicity in normal tissues expressing low-level NKG2D ligands. Overall, elucidating ULBP1 biology provides a strong foundation for exploiting NKG2D-mediated immunity in cancer therapy and represents an active research frontier in tumor immunology.

References

Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3(10):781–790.
Eagle RA, Trowsdale J. Promiscuity and the single receptor: NKG2D. Nat Rev Immunol. 2007;7(9):737–744.
Han J, Wang Y, Chan GC, et al. Designs of NKG2D-based immunotherapeutics for cancer. Front Immunol. 2025 Jun 19;16:1557644.

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