The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2005, Vol.22 (1), p.59-70
• Main Authors: Yu, Yanxing, Wang, Shizhen Emily, Hayward, Gary S.
• Format: Article
• Language: English
• Subjects: Deoxyribonucleic acid; DNA; DNA-Binding Proteins - metabolism; Enzymes; Gene Expression Regulation, Viral; Genes; Genetic Vectors; HeLa Cells; Herpesvirus 8, Human - genetics; Humans; Interferon Regulatory Factor-7; Kaposi's sarcoma-associated herpesvirus; Mutagenesis, Site-Directed; Phosphorylation; Plasmids; Promoter Regions, Genetic; Protein Binding; Proteins; Substrate Specificity; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Transfection; Tumor Cells, Cultured; Ubiquitin-Protein Ligases - metabolism; Virus Activation
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2004.11.011

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 IFNα and IFNβ 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.