{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nULBP1 is a member of the UL16‐binding protein family that functions as a stress‐inducible ligand for the activating receptor NKG2D expressed on natural killer (NK) cells and certain T lymphocytes. Engagement of ULBP1 on target cells can trigger robust cytotoxic responses against infected, transformed, or otherwise stressed cells, and its cell surface display is influenced by its biochemical characteristics including anchorage via glycosylphosphatidylinositol (GPI) and its partitioning into lipid raft microdomains that optimize NK cell immune synapse formation. Studies have also established that the transcriptional control of ULBP1 expression is critical for its immune function, as demonstrated by promoter analyses and investigations into its regulated expression on antigen‐presenting cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as an immunostimulatory ligand, ULBP1 expression is tightly regulated by a variety of cellular stress signals and transcription factors. Oncogenic and DNA damage–related pathways contribute to its upregulation—for instance, wild‐type p53 activation has been shown to increase ULBP1 transcription, while c-Myc and ATF4 have been implicated in modulating its expression in leukemic cells. In parallel, certain viral proteins manipulate ULBP1 levels to evade immune recognition, with examples including HIV-1 Vpr–mediated induction and polyomavirus as well as cytomegalovirus strategies that delay or downregulate its surface expression. In addition, the lipid microenvironment, as indicated by the necessity for proper lipid raft localization, further modulates the extent to which ULBP1 can effectively signal to NKG2D, thereby influencing immune cell cytotoxicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its immunological roles, ULBP1 has been linked to non‐classical functions that impact other biological processes. For example, aberrant expression of ULBP1 has been associated with altered trophoblast invasion, likely through modulation of autophagic pathways and TNF-α signaling in the context of pregnancy disorders, and with impaired osteoblast differentiation in conditions such as osteoporosis. Viral regulatory proteins may also affect ULBP1 promoter activity, further highlighting its role as a dynamic molecular switch at the intersection of immunity and cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claire L Sutherland, N Jan Chalupny, Kenneth Schooley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.168.2.671"}], "href": "https://doi.org/10.4049/jimmunol.168.2.671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11777960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11777960"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alexander Rölle, Mehrdad Mousavi-Jazi, Mikael Eriksson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.171.2.902"}], "href": "https://doi.org/10.4049/jimmunol.171.2.902"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12847260"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12847260"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Konstantina Eleme, Sabrina B Taner, Björn Onfelt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20032194"}], "href": "https://doi.org/10.1084/jem.20032194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15051759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15051759"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alejandro López-Soto, Adolfo Quiñones-Lombraña, Rubén López-Arbesú, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of ULBP1, a human ligand of the NKG2D receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M604868200"}], "href": "https://doi.org/10.1074/jbc.M604868200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16901903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16901903"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "San-fang Tu, Kun-yuan Guo, Liang-shan Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Expression of NKG2D ligands on dendritic cells at different development stages and its effect on cytotoxicity of NK cells]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (2008)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18394338"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18394338"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hong-fang Ma, Xiang He, Ke Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[The construction of reporter plasmid of ULBP1 and preliminary studying on the influence of NS3/4A on transcription of ULBP1]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19500498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19500498"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jeffrey Ward, Zachary Davis, Jason DeHart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1000613"}], "href": "https://doi.org/10.1371/journal.ppat.1000613"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19798433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19798433"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ayman Antoun, Shirley Jobson, Mark Cook, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Single nucleotide polymorphism analysis of the NKG2D ligand cluster on the long arm of chromosome 6: Extensive polymorphisms and evidence of diversity between human populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.humimm.2010.02.018"}], "href": "https://doi.org/10.1016/j.humimm.2010.02.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20219610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20219610"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Emily Martinez, Joseph A Brzostowski, Eric O Long, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cutting edge: NKG2D-dependent cytotoxicity is controlled by ligand distribution in the target cell membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1002254"}], "href": "https://doi.org/10.4049/jimmunol.1002254"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21464092"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21464092"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Sonja Textor, Nathalie Fiegler, Annette Arnold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-10-3211"}], "href": "https://doi.org/10.1158/0008-5472.CAN-10-3211"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21764762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21764762"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Arash Nanbakhsh, Cécile Pochon, Aude Mallavialle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2013-11-536219"}], "href": "https://doi.org/10.1182/blood-2013-11-536219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24677544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24677544"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Stefan Gundermann, Erdwine Klinker, Brigitte Kimmel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A comprehensive analysis of primary acute myeloid leukemia identifies biomarkers predicting susceptibility to human allogeneic Vγ9Vδ2 T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunother (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/CJI.0000000000000043"}], "href": "https://doi.org/10.1097/CJI.0000000000000043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24911793"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24911793"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Benjamin G Gowen, Bryan Chim, Caleb D Marceau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.08474"}], "href": "https://doi.org/10.7554/eLife.08474"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26565589"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26565589"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yoav Bauman, Nir Drayman, Orly Ben-Nun-Shaul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of the stress-induced ligand ULBP1 following SV40 infection confers viral evasion from NK cell cytotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.8085"}], "href": "https://doi.org/10.18632/oncotarget.8085"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26992229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26992229"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jing Liu, Guang Song, Tao Meng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UL16-Binding Protein 1 Induced HTR-8/SVneo Autophagy via NF-"}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "κ"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "B Suppression Mediated by TNF-"}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "α"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Secreted through uNK Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2020/9280372"}], "href": "https://doi.org/10.1155/2020/9280372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32626772"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32626772"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Sirwan Sleman, Hongyun Hao, Hastyar Najmuldeen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human Cytomegalovirus UL24 and UL43 Cooperate to Modulate the Expression of Immunoregulatory UL16 Binding Protein 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Viral Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/vim.2022.0041"}], "href": "https://doi.org/10.1089/vim.2022.0041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36179070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36179070"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Zhen Lai, Mingming Li, Xiaodong Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of the UL-16 binding protein 1 promotes osteoblast differentiation of human mesenchymal stem cells by activating the SMAD2/3 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Musculoskelet Disord (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12891-024-07341-0"}], "href": "https://doi.org/10.1186/s12891-024-07341-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38481217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38481217"}]}]}]}