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Gene Review

ULBP1  -  UL16 binding protein 1

Homo sapiens

Synonyms: ALCAN-beta, N2DL-1, N2DL1, NKG2D ligand 1, NKG2DL1, ...
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Disease relevance of ULBP1

  • We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice [1].
  • Results show that the HIV-1 Nef protein downmodulates cell-surface expression of MICA, ULBP1 and ULBP2, with a stronger effect on the latter molecule [2].
  • The human cytomegalovirus UL16 protein is known to disrupt the ULBP-NKG2D interaction, thereby subverting natural killer cell-mediated responses [3].
  • We show that the mouse cytomegalovirus (MCMV) molecule fcr-1 promotes a rapid down-regulation of NKG2D ligands murine UL16-binding protein like transcript (MULT)-1 and H60 from the cell surface [4].
  • Indeed, leukemic T cells as well as certain B-cell lymphomas were killed in a NKG2D-dependent fashion upon recognition of ULBP molecules [5].

High impact information on ULBP1

  • Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus-infected cells might evade attack by the immune system [6].
  • Ad5-E1A, but not E1A-Deltap300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants [7].
  • Patches of cross-linked raft resident ganglioside GM1 colocalized with ULBP1, 2, 3, or MICA, but not CD45 [8].
  • Cell surface proteins major histocompatibility complex (MHC) class I-related chain A (MICA) and UL16-binding proteins (ULBP) 1, 2, and 3 are up-regulated upon infection or tumor transformation and can activate human natural killer (NK) cells [8].
  • Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D [8].

Chemical compound and disease context of ULBP1


Biological context of ULBP1

  • Furthermore, TLR2 contributes to up-regulation of ULBP1 expression [10].
  • The mutation or deletion of this Sp1/Sp3 binding site abolished the transcription of ULBP1 [11].
  • It also diminished the transactivation of ULBP1 promoter by Sp3 overexpression, but not by Sp1, indicating that Sp3 is the main transcription factor that regulates ULBP1 through the CRE(1) site [11].
  • The activating receptor, NKG2D, is expressed on a variety of immune effector cells and recognizes divergent families of major histocompatibility complex (MHC) class I-related ligands, including the MIC and ULBP proteins [12].
  • Given the importance of the ULBPs in antiviral immunity in other species, our goal was to determine the copy number and genomic organization of the ULBP genes in the cattle genome [3].

Anatomical context of ULBP1


Associations of ULBP1 with chemical compounds

  • Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor [11].
  • In addition, we demonstrate that the tyrosine kinase activity repression results in a decrease of MHC-related Ags-A/B and UL-16-binding protein expression on Bcr/Abl transfectants UT-7/9 [15].

Physical interactions of ULBP1

  • This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG2D, an activating receptor expressed by all NK cells [2].

Regulatory relationships of ULBP1

  • On the contrary, NKG2D triggering of these CD8+ T cell clones induced recognition of allogeneic CRC lines showing high expression of MICA and ULBP [16].
  • In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation [17].

Other interactions of ULBP1

  • Treatment with differentiation-promoting myeloid growth factors, together with interferon-gamma, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis [18].
  • UL16 expression has been shown to promote intracellular accumulation of MICB, ULBP1 and 2 and thus, interfere with the immune response to HCMV-infected cells [19].
  • Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP [13].
  • We characterized two novel members of the RAET1/ULBP gene cluster, RAET1E and RAET1G [20].
  • Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies [21].

Analytical, diagnostic and therapeutic context of ULBP1


  1. ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. Sutherland, C.L., Rabinovich, B., Chalupny, N.J., Brawand, P., Miller, R., Cosman, D. Blood (2006) [Pubmed]
  2. Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity. Cerboni, C., Neri, F., Casartelli, N., Zingoni, A., Cosman, D., Rossi, P., Santoni, A., Doria, M. J. Gen. Virol. (2007) [Pubmed]
  3. Genomic organization and evolution of the ULBP genes in cattle. Larson, J.H., Marron, B.M., Beever, J.E., Roe, B.A., Lewin, H.A. BMC Genomics (2006) [Pubmed]
  4. The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60. Lenac, T., Budt, M., Arapovic, J., Hasan, M., Zimmermann, A., Simic, H., Krmpotic, A., Messerle, M., Ruzsics, Z., Koszinowski, U.H., Hengel, H., Jonjic, S. J. Exp. Med. (2006) [Pubmed]
  5. Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Pende, D., Rivera, P., Marcenaro, S., Chang, C.C., Biassoni, R., Conte, R., Kubin, M., Cosman, D., Ferrone, S., Moretta, L., Moretta, A. Cancer Res. (2002) [Pubmed]
  6. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Cosman, D., Müllberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., Chalupny, N.J. Immunity (2001) [Pubmed]
  7. Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection. Routes, J.M., Ryan, S., Morris, K., Takaki, R., Cerwenka, A., Lanier, L.L. J. Exp. Med. (2005) [Pubmed]
  8. Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D. Eleme, K., Taner, S.B., Onfelt, B., Collinson, L.M., McCann, F.E., Chalupny, N.J., Cosman, D., Hopkins, C., Magee, A.I., Davis, D.M. J. Exp. Med. (2004) [Pubmed]
  9. ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Kubin, M., Cassiano, L., Chalupny, J., Chin, W., Cosman, D., Fanslow, W., Müllberg, J., Rousseau, A.M., Ulrich, D., Armitage, R. Eur. J. Immunol. (2001) [Pubmed]
  10. Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium. Vankayalapati, R., Garg, A., Porgador, A., Griffith, D.E., Klucar, P., Safi, H., Girard, W.M., Cosman, D., Spies, T., Barnes, P.F. J. Immunol. (2005) [Pubmed]
  11. Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor. L??pez-Soto, A., Qui??ones-Lombra??a, A., L??pez-Arbes??, R., L??pez-Larrea, C., Gonz??lez, S. J. Biol. Chem. (2006) [Pubmed]
  12. Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. Dunn, C., Chalupny, N.J., Sutherland, C.L., Dosch, S., Sivakumar, P.V., Johnson, D.C., Cosman, D. J. Exp. Med. (2003) [Pubmed]
  13. Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Hanaoka, N., Kawaguchi, T., Horikawa, K., Nagakura, S., Mitsuya, H., Nakakuma, H. Blood (2006) [Pubmed]
  14. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Raffaghello, L., Prigione, I., Airoldi, I., Camoriano, M., Levreri, I., Gambini, C., Pende, D., Steinle, A., Ferrone, S., Pistoia, V. Neoplasia (2004) [Pubmed]
  15. The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation. Cebo, C., Da Rocha, S., Wittnebel, S., Turhan, A.G., Abdelali, J., Caillat-Zucman, S., Bourhis, J.H., Chouaib, S., Caignard, A. J. Immunol. (2006) [Pubmed]
  16. NKG2D engagement of colorectal cancer-specific T cells strengthens TCR-mediated antigen stimulation and elicits TCR independent anti-tumor activity. Maccalli, C., Pende, D., Castelli, C., Mingari, M.C., Robbins, P.F., Parmiani, G. Eur. J. Immunol. (2003) [Pubmed]
  17. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. Sutherland, C.L., Chalupny, N.J., Schooley, K., VandenBos, T., Kubin, M., Cosman, D. J. Immunol. (2002) [Pubmed]
  18. Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Nowbakht, P., Ionescu, M.C., Rohner, A., Kalberer, C.P., Rossy, E., Mori, L., Cosman, D., De Libero, G., Wodnar-Filipowicz, A. Blood (2005) [Pubmed]
  19. The human cytomegalovirus glycoprotein UL16 traffics through the plasma membrane and the nuclear envelope. Valés-Gómez, M., Winterhalter, A., Roda-Navarro, P., Zimmermann, A., Boyle, L., Hengel, H., Brooks, A., Reyburn, H.T. Cell. Microbiol. (2006) [Pubmed]
  20. Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. Bacon, L., Eagle, R.A., Meyer, M., Easom, N., Young, N.T., Trowsdale, J. J. Immunol. (2004) [Pubmed]
  21. The switch from latent to productive infection in epstein-barr virus-infected B cells is associated with sensitization to NK cell killing. Pappworth, I.Y., Wang, E.C., Rowe, M. J. Virol. (2007) [Pubmed]
  22. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. André, P., Castriconi, R., Espéli, M., Anfossi, N., Juarez, T., Hue, S., Conway, H., Romagné, F., Dondero, A., Nanni, M., Caillat-Zucman, S., Raulet, D.H., Bottino, C., Vivier, E., Moretta, A., Paul, P. Eur. J. Immunol. (2004) [Pubmed]
  23. NKG2D ligands are expressed on stressed human airway epithelial cells. Borchers, M.T., Harris, N.L., Wesselkamper, S.C., Vitucci, M., Cosman, D. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  24. MHC class I-like genes in cattle, MHCLA, with similarity to genes encoding NK cell stimulatory ligands. Larson, J.H., Rebeiz, M.J., Stiening, C.M., Windish, R.L., Beever, J.E., Lewin, H.A. Immunogenetics (2003) [Pubmed]
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