Affinage

ULBP1

UL16-binding protein 1 · UniProt Q9BZM6

Length
244 aa
Mass
28.0 kDa
Annotated
2026-04-28
27 papers in source corpus 20 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ULBP1 is a GPI-anchored MHC class I-related cell-surface glycoprotein that serves as a stress-induced ligand for the activating receptor NKG2D on NK cells and γδ T cells, triggering cytotoxicity, degranulation, and IFN-γ production (PMID:11465099, PMID:20101024, PMID:21764762). Its surface expression is controlled at multiple levels: transcriptionally by Sp3 (via a CRE1 promoter element), p53 (via intronic response elements), c-Myc (direct binding to the ULBP1 locus), and ATF4; post-transcriptionally by AU-rich elements and microRNAs in its 3′ UTR and by the RNA-binding protein RBM4, which suppresses an alternatively spliced isoform (PMID:16901903, PMID:21764762, PMID:24677544, PMID:26565589, PMID:21406206). ULBP1 is distinguished from other NKG2D ligands by its rapid post-internalization proteasomal degradation, which limits its surface half-life and can be pharmacologically reversed by proteasome inhibitors (PMID:26732147, PMID:19414815). Viruses exploit ULBP1 regulation to evade immune surveillance: HCMV UL16 retains ULBP1 in the ER, and HHV-6B U20 masks surface ULBP1 from NKG2D engagement (PMID:12847260, PMID:38953028).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Establishing ULBP1 as an NKG2D ligand that activates NK cells resolved how UL16-binding proteins translate stress signals into innate immune recognition.

    Evidence Binding assays, NK cytotoxicity/cytokine/proliferation assays, soluble UL16 competition experiments

    PMID:11465099

    Open questions at the time
    • NKG2D-independent roles of ULBP1 not addressed
    • structural basis of ULBP1–NKG2D interaction not determined
    • transcriptional regulation unknown
  2. 2003 High

    Demonstrating that HCMV UL16 retains ULBP1 in the ER established the first defined mechanism by which a pathogen evades NKG2D-mediated immunity by preventing ligand surface display.

    Evidence WT vs. UL16-deletion mutant HCMV infection, flow cytometry, immunofluorescence, NK cytotoxicity assays

    PMID:12847260

    Open questions at the time
    • Whether UL16 directly binds ULBP1 in cis in the ER membrane not resolved at atomic level
    • mechanism of ER retention (coat-protein signals, chaperone involvement) undefined
  3. 2006 High

    Identification of the CRE1 promoter element bound by Sp3 (activator) and AP-2α (repressor) defined the basal transcriptional logic governing ULBP1 expression.

    Evidence Promoter reporter assays, CRE1 mutagenesis, EMSA, Sp1/Sp3/AP-2α overexpression in Drosophila SL2 and HeLa cells

    PMID:16901903

    Open questions at the time
    • Chromatin context and epigenetic regulation not explored
    • how stress signals converge on Sp3/AP-2α balance unknown
  4. 2009 High

    Proteasome inhibition was shown to specifically upregulate ULBP1 transcription through its proximal promoter independently of DNA-damage signaling, separating proteasome-dependent control from ATM/ATR pathways.

    Evidence Bortezomib treatment, RT-PCR/flow cytometry, promoter reporter, ATM/ATR inhibitors across multiple cell lines

    PMID:19414815

    Open questions at the time
    • Identity of the proteasome-sensitive transcription factor acting at the ULBP1 promoter not determined
    • in vivo relevance of proteasome-dependent transcriptional regulation not tested
  5. 2011 High

    Discovery that wild-type p53 drives ULBP1 transcription via intronic response elements linked the tumor suppressor pathway to NKG2D-dependent immunosurveillance, while 3′ UTR AU-rich elements and microRNAs added a post-transcriptional regulatory layer.

    Evidence p53 induction, intronic response element mapping, NK degranulation/IFN-γ assays, NKG2D blocking (p53 arm); 3′ UTR reporter constructs, ARE mutagenesis, microRNA overexpression (post-transcriptional arm)

    PMID:21406206 PMID:21764762

    Open questions at the time
    • Relative contributions of p53-dependent transcription vs. microRNA repression in physiological settings not quantified
    • microRNA effects not validated by individual antagomir rescue at endogenous ULBP1 protein level
  6. 2014 High

    ChIP evidence that c-Myc directly binds the ULBP1 locus and drives its expression in AML cells revealed an oncogene-dependent route to NKG2D ligand upregulation that can sensitize drug-resistant leukemia to NK killing.

    Evidence ChIP for c-Myc at ULBP1/3 loci, c-Myc inhibition, flow cytometry, NK lysis of primary AML blasts

    PMID:24677544

    Open questions at the time
    • Whether c-Myc acts through the same CRE1 or distinct promoter/enhancer elements not resolved
    • cooperation or antagonism between c-Myc and p53 at the ULBP1 locus not addressed
  7. 2015 High

    A forward genetic screen identified ATF4 as a transcriptional activator and RBM4 as a post-transcriptional regulator of ULBP1 (suppressing an aberrant splice isoform), revealing that independent pathways converge at multiple biogenesis stages.

    Evidence Forward genetic screen in tumor cells, ATF4 and RBM4 validation, alternative splicing analysis

    PMID:26565589

    Open questions at the time
    • Structure and function of the alternatively spliced ULBP1 isoform not characterized
    • whether ATF4-driven ULBP1 induction requires integrated stress response activation in vivo unknown
  8. 2016 Medium

    ULBP1 was shown to have an unusually short surface half-life due to rapid ubiquitin-proteasomal degradation after internalization, distinguishing it from other ULBPs and explaining why proteasome inhibitors preferentially boost ULBP1 surface levels.

    Evidence Surface stability assays, proteasome inhibition, shedding/internalization rate measurements, pulse-chase

    PMID:26732147

    Open questions at the time
    • E3 ligase responsible for ULBP1 ubiquitination not identified
    • sorting signals directing ULBP1 to proteasomal rather than lysosomal degradation unknown
    • single-lab finding
  9. 2018 Medium

    Celecoxib-induced ULBP1 upregulation via JNK/PI3K pathways (COX-2- and ER-stress-independent) and HCV-induced ULBP1 surface expression on hepatocytes broadened the range of stimuli and cell types activating NKG2D-mediated immunity through ULBP1.

    Evidence Celecoxib ± pathway inhibitors, flow cytometry, NK cytotoxicity (colon/lung cancer); HCV infection, ULBP1 surface detection, NK-92 co-culture, HCV RNA quantification (hepatocytes)

    PMID:25218028 PMID:29511613

    Open questions at the time
    • Direct transcription factor(s) mediating JNK/PI3K-dependent ULBP1 induction not identified
    • contradiction between NS3/4A-mediated ULBP1 suppression and HCV-induced ULBP1 upregulation not reconciled
  10. 2024 High

    HHV-6B glycoprotein U20 was shown to directly bind ULBP1 at the cell surface with sub-micromolar affinity, blocking NKG2D engagement without reducing ULBP1 levels — a viral masking strategy distinct from HCMV's ER retention mechanism.

    Evidence Recombinant protein binding, U20 transduction, NKG2D competition, NK activation assays, SAXS structural modeling

    PMID:38953028

    Open questions at the time
    • High-resolution crystal/cryo-EM structure of U20–ULBP1 complex not yet available
    • whether U20 also masks other NKG2D ligands not fully resolved
  11. 2025 Medium

    Cyclosporin A was found to induce ubiquitination-dependent proteasomal degradation of endothelial ULBP1, reducing NKG2D-mediated NK cell PI3K/AKT signaling — linking immunosuppressive drug action to ULBP1 post-translational turnover.

    Evidence CsA treatment of endothelial cells, ubiquitination assays, proteasome inhibition rescue, NK co-culture signaling and cytotoxicity assays

    PMID:41297348

    Open questions at the time
    • E3 ligase mediating CsA-induced ULBP1 ubiquitination not identified
    • whether calcineurin inhibition is the upstream trigger unknown
    • single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • The E3 ubiquitin ligase(s) targeting ULBP1 for post-internalization degradation remain unidentified, and no high-resolution structure of ULBP1 alone or in complex with NKG2D/viral evasins has been determined, limiting structure-guided therapeutic design.
  • E3 ligase identity unknown
  • high-resolution ULBP1 structure lacking despite preliminary crystallization
  • relative in vivo contributions of transcriptional vs. post-translational regulation not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4
Localization
GO:0005886 plasma membrane 7 GO:0005576 extracellular region 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3
Partners
ATF4KLRK1MYCRBM4SP3TP53U20UL16

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ULBP1, ULBP2, and ULBP3 are novel MHC class I-related molecules that bind human cytomegalovirus glycoprotein UL16 and activate NK cells, inducing cytokine/chemokine production, proliferation, cytotoxic activity, and upregulation of activation-associated surface molecules. Soluble recombinant UL16 protein inhibited ULBP-mediated biological activities, establishing a viral immune evasion mechanism. Binding assays, NK cell functional assays (cytokine production, cytotoxicity, proliferation), competition experiments with soluble UL16 European journal of immunology High 11465099
2003 HCMV glycoprotein UL16 retains ULBP1 and ULBP2 in the endoplasmic reticulum of infected cells, preventing their surface expression and thereby limiting NKG2D-dependent NK cell recognition. Infection with a UL16 deletion mutant virus resulted in surface expression of all three ULBPs and a pronounced, entirely NKG2D-dependent increase in NK sensitivity. Viral infection with wild-type vs. UL16-deletion mutant HCMV, flow cytometry for surface expression, NK cell cytotoxicity assays, immunofluorescence/subcellular localization Journal of immunology High 12847260
2006 ULBP1 transcription is driven by binding of Sp1 and Sp3 to a CRE(1) site in the ULBP1 minimal promoter, with Sp3 being the essential activator (>500-fold upregulation upon Sp3 overexpression in SL2 cells). AP-2alpha represses ULBP1 expression by interfering with Sp1/Sp3 binding to the ULBP1 promoter. Promoter reporter assays, site-directed mutagenesis of the CRE(1) site, Sp1/Sp3/AP-2alpha overexpression, EMSA, transcription factor binding studies in SL2 (Drosophila) cells and HeLa cells The Journal of biological chemistry High 16901903
2006 ULBP1 is expressed on mature dendritic cells both in situ in lymph node T cell areas and in vitro after artificial maturation, suggesting a role for NKG2D-ULBP1 in initiation or reactivation of T cell responses. Flow cytometry, in situ detection in sentinel lymph nodes, in vitro DC maturation assays European journal of immunology Medium 16342232
2009 Proteasome inhibition (by bortezomib and other proteasome inhibitors) dramatically and specifically upregulates ULBP1 mRNA and cell surface protein by acting at a site within the 522-bp ULBP1 promoter, through a mechanism independent of ATM/ATR DNA damage signaling. Proteasome inhibitor treatment, ULBP1 mRNA/surface protein measurement by RT-PCR and flow cytometry, promoter reporter assays, ATM/ATR inhibitor experiments, pharmacological and radiation treatments Journal of immunology High 19414815
2009 HCV protease NS3/4A inhibits ULBP1 transcription, as demonstrated by reduced luciferase activity from a ULBP1 promoter reporter construct co-transfected with NS3/4A expression plasmid. Luciferase reporter assay with ULBP1 promoter construct, NS3/4A expression vector co-transfection Xi bao yu fen zi mian yi xue za zhi Low 19500498
2010 ULBP1 expression levels are a nonredundant determinant of lymphoma susceptibility to gammadelta T cell-mediated cytolysis; NKG2D blockade significantly inhibits lymphoma killing, and specific ULBP1 loss-of-function reduces gammadelta T cell cytotoxicity against lymphoma cells. NKG2D blocking antibodies, ULBP1-specific siRNA knockdown, cytotoxicity assays with primary gammadelta T cells, flow cytometry Blood High 20101024
2011 Wild-type p53, but not mutant p53, strongly upregulates ULBP1 and ULBP2 mRNA and cell surface expression via intronic p53-responsive elements in these genes, enhancing NKG2D-dependent NK cell degranulation and IFN-γ production. p53 induction in human tumor cells, RT-PCR and flow cytometry for ULBP1/2 expression, identification of intronic p53-responsive elements, NK cell degranulation and IFN-γ assays, NKG2D blocking, p53-reactivating compound RITA treatment Cancer research High 21764762
2011 The 3' UTR of ULBP1 mRNA mediates post-transcriptional repression; AU-rich elements (ARE) within the 3' UTR have an mRNA-stabilizing effect when mutated, and specific microRNAs (miR-140-5p, miR-409-3p, miR-433-3p, miR-650) expressed in HeLa and Jurkat cells may contribute to ULBP1 regulation. Luciferase reporter assays with full-length and truncated ULBP1 3' UTR constructs, ARE mutagenesis, microRNA overexpression, Drosha partial silencing Human immunology Medium 21406206
2014 c-Myc directly binds the ULBP1 and ULBP3 gene loci and regulates their expression; cytarabine-resistant AML cells exhibit c-Myc induction driving ULBP1/2/3 upregulation and increased susceptibility to NK-mediated lysis, reversed by c-Myc inhibition. Chromatin immunoprecipitation (ChIP) assay for c-Myc binding to ULBP1/3 loci, c-Myc inhibition, flow cytometry for NKG2D ligand expression, NK cell lysis assays with primary AML blasts Blood High 24677544
2015 A forward genetic screen identified ATF4 as a transcription factor that drives ULBP1 gene expression in cancer cell lines, and RNA-binding protein RBM4 supports ULBP1 expression by suppressing a novel alternatively spliced isoform of ULBP1 mRNA, revealing that independent pathways work at multiple stages of ULBP1 biogenesis. Forward genetic screen in tumor-derived human cell line, identification and validation of ATF4 and RBM4 as regulators, alternative splicing analysis eLife High 26565589
2016 ULBP1 has a shorter half-life at the cell surface than other ULBP molecules due to rapid proteasomal degradation following internalization, not due to shedding or increased internalization rate; proteasome inhibition blocks this post-internalization degradation. Surface stability assays, proteasome inhibitors, shedding assays, internalization assays, pulse-chase experiments Immunology and cell biology Medium 26732147
2016 SV40 infection downregulates ULBP1 surface expression, allowing viral evasion from NK cell cytotoxicity mediated through NKG2D. SV40 infection of target cells, flow cytometry for ULBP1 surface expression, NK cell cytotoxicity assays Oncotarget Medium 26992229
2018 Hepatitis C virus infection induces cell surface expression of ULBP1 in human hepatocytes, and NK cells (NK-92 line) recognize HCV-infected cells via NKG2D-ULBP1 interaction, triggering cytotoxicity and IFN-γ expression that reduces HCV RNA replication. HCV infection of PH5CH8 and RSc cells, flow cytometry for ULBP1, NK-92 co-culture cytotoxicity and IFN-γ assays, HCV RNA quantification FEBS open bio Medium 29511613
2018 Celecoxib induces ULBP-1 expression in colon cancer cells via COX-2-independent and ER stress-independent pathways, increasing susceptibility to NK cell-mediated cytotoxicity in both COX-2 negative and positive cell lines. Celecoxib treatment with/without COX-2 inhibition or ER stress induction (thapsigargin), flow cytometry for ULBP-1, DELFIA NK cytotoxicity assay, soft agar colony forming assay Experimental cell research Medium 25218028
2020 Celecoxib upregulates ULBP-1 expression in lung cancer cells via JNK and PI3K signaling pathways (both inhibited by respective pathway inhibitors), and this ULBP-1 induction increases susceptibility to NK cell-mediated cytotoxicity. Celecoxib treatment with JNK/PI3K inhibitors, PCR and immunoblotting for ULBP-1, flow cytometry, NK cell cytotoxicity assay, fluorescence microscopy Oncology letters Medium 33014157
2021 Tanshinone IIA increases ULBP1 expression in NSCLC cells via ATF4 (downstream of p-PERK), as ATF4 knockdown completely reverses ULBP1 upregulation; this ULBP1 induction mediates enhanced NK cell cytotoxicity. TIIA treatment, ATF4/CHOP siRNA knockdown, immunoblotting for p-PERK/ATF4/CHOP, flow cytometry for ULBP1, NK cell cytotoxicity assay, in vivo syngeneic and xenograft mouse models with NK cell depletion Journal of leukocyte biology Medium 33909909
2024 HHV-6B glycoprotein U20 binds directly to ULBP1 with sub-micromolar affinity, masking it from NKG2D recognition at the cell surface without reducing ULBP1 protein levels, thereby blocking NK cell activation. Recombinant protein binding assays, U20 transduction into target cells, NKG2D binding competition assay, NK cell activation assays, small-angle X-ray scattering (SAXS) for structural modeling of U20-ULBP1 complex Frontiers in immunology High 38953028
2025 Cyclosporin A (CsA) induces ubiquitination-dependent proteasomal degradation of endothelial ULBP1, reducing NKG2D ligand availability and thereby weakening NK cell PI3K/AKT signaling and effector function in renal microvascular inflammation. CsA treatment of endothelial cells, co-culture with NK cells, ubiquitination assays, proteasome inhibition, PI3K/AKT signaling measurement, NK cell activation/cytotoxicity assays International immunopharmacology Medium 41297348
2024 SIRT4 activates AMPKα to promote p53 phosphorylation and nuclear translocation, which induces transcription of ULBP1 (and ULBP2), thereby enhancing NK cell cytotoxicity against activated hepatic stellate cells. SIRT4 overexpression/knockdown, AMPKα activation assays, p53 phosphorylation and nuclear translocation assays, ULBP1/2 transcription measurement, NK cell cytotoxicity assays, AAV-mediated SIRT4 delivery in mouse LF models bioRxivpreprint Medium
2011 Recombinant ULBP1 extracellular domain was successfully expressed in E. coli, refolded, and crystallized, yielding initial X-ray diffraction data to 4.6 Å, establishing conditions for structural characterization of the protein. Recombinant protein expression in E. coli, refolding from inclusion bodies, site-directed mutagenesis of unpaired cysteines, size exclusion and ion exchange chromatography, X-ray crystallography Protein expression and purification Low 21575723

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer research 181 21764762
2003 Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: up-regulation of UL16-binding protein (ULBP)1 and ULBP2 is counteracted by the viral UL16 protein. Journal of immunology (Baltimore, Md. : 1950) 131 12847260
2001 ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. European journal of immunology 123 11465099
2010 The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to gammadelta T-cell cytotoxicity. Blood 109 20101024
2009 Proteasome regulation of ULBP1 transcription. Journal of immunology (Baltimore, Md. : 1950) 62 19414815
2006 Transcriptional regulation of ULBP1, a human ligand of the NKG2D receptor. The Journal of biological chemistry 58 16901903
2014 c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis. Blood 45 24677544
2015 A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells. eLife 40 26565589
2020 Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer medicine 34 32077634
2016 Downregulation of the stress-induced ligand ULBP1 following SV40 infection confers viral evasion from NK cell cytotoxicity. Oncotarget 24 26992229
2021 Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma. Frontiers in oncology 23 34568062
2011 Post-transcriptional regulation of ULBP1 ligand for the activating immunoreceptor NKG2D involves 3' untranslated region. Human immunology 21 21406206
2006 Expression of the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cells. European journal of immunology 21 16342232
2016 A short half-life of ULBP1 at the cell surface due to internalization and proteosomal degradation. Immunology and cell biology 18 26732147
2021 Tanshinone IIA enhances susceptibility of non-small cell lung cancer cells to NK cell-mediated lysis by up-regulating ULBP1 and DR5. Journal of leukocyte biology 15 33909909
2020 ULBP1 Is Elevated in Human Hepatocellular Carcinoma and Predicts Outcome. Frontiers in oncology 15 32656081
2014 COX-2- and endoplasmic reticulum stress-independent induction of ULBP-1 and enhancement of sensitivity to NK cell-mediated cytotoxicity by celecoxib in colon cancer cells. Experimental cell research 15 25218028
2020 Celecoxib upregulates ULBP-1 expression in lung cancer cells via the JNK/PI3K signaling pathway and increases susceptibility to natural killer cell cytotoxicity. Oncology letters 11 33014157
2018 ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell-mediated innate immune response in human hepatocytes. FEBS open bio 9 29511613
2024 Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma. Cancers 7 39199623
2024 Human esophageal cancer stem-like cells escape the cytotoxicity of natural killer cells via down-regulation of ULBP-1. Journal of translational medicine 5 39103915
2024 The HHV-6B U20 glycoprotein binds ULBP1, masking it from recognition by NKG2D and interfering with natural killer cell activation. Frontiers in immunology 3 38953028
2020 Production of a novel bispecific protein ULBP1×CD19-scFv targeting the NKG2D receptor and CD19 to promote the activation of NK cells. Protein expression and purification 1 33122138
2025 Cyclosporin A indirectly suppresses NK cells activity in renal microvascular inflammation by inducing ubiquitination-dependent degradation of ULBP1. International immunopharmacology 0 41297348
2023 Dynamics of Soluble Forms of the Immune Checkpoint Components PD-1/PD-L1/B7-H3, CD314/ULBP1, and HLA-G in Peripheral Blood of Melanoma Patients Receiving Blockers of Programmed Cell Death Protein PD-1. Bulletin of experimental biology and medicine 0 37773572
2011 Expression, purification and crystallization of the human UL16-binding protein ULBP1. Protein expression and purification 0 21575723
2009 [The construction of reporter plasmid of ULBP1 and preliminary studying on the influence of NS3/4A on transcription of ULBP1]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 19500498