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

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-kappa B 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-kappa B 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-kappa b 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.