title: The N-terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression.
abstract: Ag presentation to CD4(+) and CD8(+) T cells depends on MHC class II and MHC class I molecules, respectively. One important regulatory factor of this process is the transcriptional regulation of MHC gene expression. It is well established that MHC class II transcription relies on the NLR protein CIITA. Recently, another NLR protein, NLRC5, was shown to drive MHC class I expression. The molecular mechanisms of the function of NLRC5 however remain largely elusive. In this study, we present a detailed functional study of the domains of NLRC5 revealing that the N-terminal domain of human NLRC5 has intrinsic transcriptional activity. Domain swapping experiments between NLRC5 and CIITA showed that this domain contributes to MHC class I and MHC class II gene expression with a bias for activation of MHC class I promoters. Delivery of this construct by adeno-associated viral vectors upregulated MHC class I and MHC class II expression in human cells and enhanced lysis of melanoma cells by CD8(+) cytotoxic T cells in vitro. Taken together, this work provides novel insight into the function of NLRC5 and CIITA in MHC gene regulation.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Neerincx
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany;
authors.forename: Kristin
authors.initials: K
authors.lastname: Jakobshagen
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, partner site Bonn-Cologne; Department I of Internal Medicine, University of Cologne, 50937 Cologne, Germany; and.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
authors.affiliation: Département de Biologie, Université de Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada.
authors.forename: Viktor
authors.initials: V
authors.lastname: Steimle
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany; thomas.kufer@uk-koeln.de.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; C083728:MHC class II transactivator protein; C548042:NLRC5 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators