Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi's sarcoma-associated herpesvirus viral IRF homolog vIRF3.
Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated antiviral pathway that is mediated by IFN regulatory factors (IRFs). In order to complete their life cycle, viruses must modulate the host IFN-mediated immune response. Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor-inducing herpesvirus, has developed a unique mechanism for antagonizing cellular IFN-mediated antiviral activity by incorporating viral homologs of the cellular IRFs, called vIRFs. Here, we report a novel immune evasion mechanism of KSHV vIRF3 to block cellular IRF7-mediated innate immunity in response to viral infection. KSHV vIRF3 specifically interacts with either the DNA binding domain or the central IRF association domain of IRF7, and this interaction leads to the inhibition of IRF7 DNA binding activity and, therefore, suppression of alpha interferon (IFN-alpha) production and IFN-mediated immunity. Remarkably, the central 40 amino acids of vIRF3, containing the double alpha helix motifs, are sufficient not only for binding to IRF7, but also for inhibiting IRF7 DNA binding activity. Consequently, the expression of the double alpha helix motif-containing peptide effectively suppresses IRF7-mediated IFN-alpha production. This demonstrates a remarkably efficient means of viral avoidance of host antiviral activity.
Joo
Chul Hyun
CH
Tumor Virology Division, New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772, USA.
Shin
Young C
YC
Gack
Michaela
M
Wu
Liguo
L
Levy
David
D
Jung
Jae U
JU
D000595:Amino Acid Sequence; D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012514:Sarcoma, Kaposi; D015398:Signal Transduction / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D014764:Viral Proteins; D007372:Interferons