title: NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner.
abstract: Nucleotide-binding domain and leucine-rich repeat (NLR) proteins play important roles in innate immune responses as pattern-recognition receptors. Although most NLR proteins act in cell autonomous immune pathways, some do not function as classical pattern-recognition receptors. One such NLR protein is the MHC class II transactivator, the master regulator of MHC class II gene transcription. In this article, we report that human NLRC5, which we recently showed to be involved in viral-mediated type I IFN responses, shuttles to the nucleus and activates MHC class I gene expression. Knockdown of NLRC5 in different human cell lines and primary dermal fibroblasts leads to reduced MHC class I expression, whereas introduction of NLRC5 into cell types with very low expression of MHC class I augments MHC class I expression to levels comparable to those found in lymphocytes. Expression of NLRC5 positively correlates with MHC class I expression in human tissues. Functionally, we show that both the N-terminal effector domain of NLRC5 and its C-terminal leucine-rich repeat domain are needed for activation of MHC class I expression. Moreover, nuclear shuttling and function depend on a functional Walker A motif. Finally, we identified a promoter sequence in the MHC class I promoter, the X1 box, to be involved in NLRC5-mediated MHC class I gene activation. Taken together, this suggested that NLRC5 acts in a manner similar to class II transactivator to drive MHC expression and revealed NLRC5 as an important regulator of basal MHC class I expression.
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.forename: Galaxia M
authors.initials: GM
authors.lastname: Rodriguez
authors.forename: Viktor
authors.initials: V
authors.lastname: Steimle
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015234:HLA-A Antigens / Q000235:genetics / Q000502:physiology*; D015235:HLA-B Antigens / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D015534:Trans-Activators