Mechanisms of autoinhibition of IRF-7 and a probable model for inactivation of IRF-7 by Kaposi's sarcoma-associated herpesvirus protein ORF45.
IRF-7 is the master regulator of type I interferon-dependent immune responses controlling both innate and adaptive immunity. Given the significance of IRF-7 in the induction of immune responses, many viruses have developed strategies to inhibit its activity to evade or antagonize host antiviral responses. We previously demonstrated that ORF45, a KSHV immediate-early protein as well as a tegument protein of virions, interacts with IRF-7 and inhibits virus-mediated type I interferon induction by blocking IRF-7 phosphorylation and nuclear translocation (Zhu, F. X., King, S. M., Smith, E. J., Levy, D. E., and Yuan, Y. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 5573-5578). In this report, we sought to reveal the mechanism underlying the ORF45-mediated inactivation of IRF-7. We found that ORF45 interacts with the inhibitory domain of IRF-7. The most striking feature in the IRF-7 inhibitory domain is two α-helices H3 and H4 that contain many hydrophobic residues and two β-sheets located between the helices that are also very hydrophobic. These hydrophobic subdomains mediate intramolecular interactions that keep the molecule in a closed (inactive) form. Mutagenesis studies confirm the contribution of the hydrophobic helices and sheets to the autoinhibition of IRF-7 in the absence of viral signal. The binding of ORF45 to the critical domain of IRF-7 leads to a hypothesis that ORF45 may maintain the IRF-7 molecule in the closed form and prevent it from being activated in response to viral infection.
Sathish
Narayanan
N
Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104, USA.
Zhu
Fan Xiu
FX
Golub
Ellis E
EE
Liang
Qiming
Q
Yuan
Yan
Y
D000595:Amino Acid Sequence; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D017874:Immediate-Early Proteins / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D013379:Substrate Specificity; D015533:Transcriptional Activation
D017874:Immediate-Early Proteins; D050839:Interferon Regulatory Factor-7; C456286:ORF45 protein, Kaposi's sarcoma-associated herpesvirus