title: Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis.
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.
authors.affiliation: Division 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
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Bijlmakers
authors.forename: Seshu K
authors.initials: SK
authors.lastname: Kanneganti
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics*; D007372:Interferons / Q000096:biosynthesis / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011565:Psoriasis / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology*; D012995:Solubility / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D012330:RNA, Double-Stranded; D057149:Ubiquitinated Proteins; D007372:Interferons; C477146:RNF114 protein, human; D044767:Ubiquitin-Protein Ligases; D011070:Poly I-C