title: The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses.
abstract: Nucleotide-binding oligomerization domain-like receptors (NLRs) are a group of intracellular proteins that mediate recognition of pathogen-associated molecular patterns or other cytosolic danger signals. Mutations in NLR genes have been linked to a variety of inflammatory diseases, underscoring their pivotal role in host defense and immunity. This report describes the genomic organization and regulation of the human NLR family member NLRC5 and aspects of cellular function of the encoded protein. We have analyzed the tissue-specific expression of NLRC5 and have characterized regulatory elements in the NLRC5 promoter region that are responsive to IFN-gamma. We show that NLRC5 is upregulated in human fibroblasts postinfection with CMV and demonstrate the role of a JAK/STAT-mediated autocrine signaling loop involving IFN-gamma. We demonstrate that overexpression and enforced oligomerization of NLRC5 protein results in activation of the IFN-responsive regulatory promoter elements IFN-gamma activation sequence and IFN-specific response element and upregulation of antiviral target genes (e.g., IFN-alpha, OAS1, and PRKRIR). Finally, we demonstrate the effect of small interfering RNA-mediated knockdown of NLRC5 on a target gene level in the context of viral infection. We conclude that NLRC5 may represent a molecular switch of IFN-gamma activation sequence/IFN-specific response element signaling pathways contributing to antiviral defense mechanisms.
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Kuenzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Simone
authors.initials: S
authors.lastname: Lipinski
authors.forename: Sascha
authors.initials: S
authors.lastname: Jung
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Helmut
authors.initials: H
authors.lastname: Fickenscher
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
mesh_terms: D000595:Amino Acid Sequence; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma