The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

• Published in: The Journal of immunology (1950) Vol. 184; no. 4; pp. 1990 - 2000
• Main Authors: Kuenzel, Sven, Till, Andreas, Winkler, Michael, Hasler, Robert, Lipinski, Simone, Jung, Sascha, Grotzinger, Joachim, Fickenscher, Helmut, Schreiber, Stefan, Rosenstiel, Philip
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.02.2010
• Subjects: Amino Acid Sequence; Caco-2 Cells; Cell Line, Tumor; Cells, Cultured; Cytomegalovirus - immunology; Fibroblasts - immunology; Fibroblasts - virology; HeLa Cells; HT29 Cells; Humans; Interferon-gamma - chemistry; Interferon-gamma - metabolism; Interferon-gamma - physiology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - isolation & purification; Intracellular Signaling Peptides and Proteins - physiology; Molecular Sequence Data; Oligodeoxyribonucleotides - genetics; Oligodeoxyribonucleotides - metabolism; Protein Binding - immunology; Protein Structure, Tertiary - genetics; Response Elements - immunology; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.0900557

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-γ. 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-γ. We demonstrate that overexpression and enforced oligomerization of NLRC5 protein results in activation of the IFN-responsive regulatory promoter elements IFN-γ activation sequence and IFN-specific response element and upregulation of antiviral target genes (e.g., IFN-α, 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-γ activation sequence/IFN-specific response element signaling pathways contributing to antiviral defense mechanisms.