title: The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation.
abstract: Many viruses encode proteins that counteract the development of the interferon (IFN)-mediated antiviral state. Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription factor encoded by Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8). Cotransfection with RTA blocked IRF7-mediated IFNalpha and IFNbeta mRNA production and promoted the ubiquitination and degradation of IRF7 protein in a proteasome-dependent fashion. Addition of RTA also promoted polyubiquitination of IRF7 in an in vitro cell free assay, demonstrating that RTA itself acts as a ubiquitin E3 ligase. RTA also autoregulated its own polyubiquitination and stability, and both activities were abolished by point mutations in a Cys plus His-rich N-terminal domain. Therefore, manipulation of the stability and function of IRF7 by the KSHV RTA transcription factor provides an unexpected regulatory strategy for circumventing the innate immune defence system.
authors.affiliation: Molecular Virology Laboratories, Viral Oncology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 2123, USA.
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Yu
authors.forename: Shizhen Emily
authors.initials: SE
authors.lastname: Wang
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hayward
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics; D006801:Humans; D050839:Interferon Regulatory Factor-7; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013379:Substrate Specificity; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014775:Virus Activation
chemical_list: D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C116742:ORF 50 transactivator; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases