title: Vigilin Regulates the Expression of the Stress-Induced Ligand MICB by Interacting with Its 5' Untranslated Region.
abstract: NK cells are part of the innate immune system, and are able to identify and kill hazardous cells. The discrimination between normal and hazardous cells is possible due to an array of inhibitory and activating receptors. NKG2D is one of the prominent activating receptors expressed by all human NK cells. This receptor binds stress-induced ligands, including human MICA, MICB, and UL16-binding proteins 1-6. The interaction between NKG2D and its ligands facilitates the elimination of cells under cellular stress, such as tumor transformation. However, the mechanisms regulating the expression of these ligands are still not well understood. Under normal conditions, the NKG2D ligands were shown to be posttranscriptionally regulated by cellular microRNAs and RNA-binding proteins (RBPs). Thus far, only the 3' untranslated regions (UTRs) of MICA, MICB, and UL16-binding protein 2 were shown to be regulated by RBPs and microRNAs, usually resulting in their downregulation. In this study we investigated whether MICB expression is controlled by RBPs through its 5'UTR. We used an RNA pull-down assay followed by mass spectrometry and identified vigilin, a ubiquitously expressed multifunctional RNA-binding protein. We demonstrated that vigilin binds and negatively regulates MICB expression through its 5'UTR. Additionally, vigilin downregulation in target cells led to a significant increase in NK cell activation against said target cells. Taken together, we have discovered a novel mode of MICB regulation.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Berhani
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel.
authors.forename: Daphna
authors.identifier: 0000-0002-8489-9986
authors.initials: D
authors.lastname: Nachmani
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yamin
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmiedel
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Bar-On
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel oferm@ekmd.huji.ac.il.
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000819:agonists; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000276:immunology*
chemical_list: D020121:5' Untranslated Regions; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C075197:high density lipoprotein binding protein