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Hum Mol Genet. 2011 Aug 15;20(16):3129-37. doi: 10.1093/hmg/ddr215. Epub 2011 May 13.

Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis.

Author information

  • 1Division of Immunology, Infection and Inflammatory Disease, King’s College London, School of Medicine at Guy’s, King’s College and St Thomas’ Hospitals, London SE1 9RT, UK. marie.bijlmakers@kcl.ac.uk

Abstract

Psoriasis is an immune-mediated skin disease, the aetiology of which remains poorly understood. In recent years, genome-wide association studies (GWAS) have helped to illuminate the molecular basis of this condition, by demonstrating the pathogenic involvement of multiple genes from the IL-23 and NF-κB pathways. A GWAS carried out by our group also identified RNF114, a gene encoding a novel ubiquitin binding protein, as a determinant for psoriasis susceptibility. Although the function of RNF114 is unknown, its paralogue RNF125 has been shown to regulate the RIG-I/MDA5 innate antiviral response. This signalling cascade, which is activated by the presence of double-stranded RNA (dsRNA) within the cytoplasm, induces the production of type I interferon (IFN) through the activation of the IRF3 and NF-κB transcription factors. Here, we explore the hypothesis that RNF114 may also modulate RIG-I/MDA5 signalling. We show that RNF114 associates with ubiquitinated proteins and that it is a soluble cytosolic protein that can be induced by interferons and synthetic dsRNA. Moreover, we demonstrate that RNF114 over-expression enhances NF-κb and IRF3 reporter activity and increases type I and type III IFN mRNA levels. These results indicate that RNF114 regulates a positive feedback loop that enhances dsRNA induced production of type I IFN. Thus, our data point to a novel pathogenic pathway, where dysregulation of RIG-I/MDA5 signalling leads to the over-production of type I IFN, a key early mediator of epithelial inflammation.

PMID:
21571784
[PubMed - indexed for MEDLINE]
PMCID:
PMC3140818
Free PMC Article

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