The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation.
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.
Yu
Yanxing
Y
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.
Wang
Shizhen Emily
SE
Hayward
Gary S
GS
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
D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C116742:ORF 50 transactivator; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases