| Mechanisms of autoinhibition of IRF-7 and a probable model for inactivation of IRF-7 by Kaposi's sarcoma-associated herpesvirus protein ORF45. | |
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MedLine Citation:
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PMID: 20980251 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Narayanan Sathish; Fan Xiu Zhu; Ellis E Golub; Qiming Liang; Yan Yuan |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-27 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-03 Completed Date: 2011-01-31 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 746-56 Citation Subset: IM |
Affiliation:
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Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence HEK293 Cells Herpesvirus 8, Human* / physiology Humans Hydrophobic and Hydrophilic Interactions Immediate-Early Proteins / metabolism* Interferon Regulatory Factor-7 / antagonists & inhibitors*, chemistry, genetics, metabolism* Models, Molecular* Molecular Sequence Data Mutagenesis Protein Structure, Secondary Protein Structure, Tertiary Sequence Deletion Substrate Specificity Transcriptional Activation |
| Grant Support | |
ID/Acronym/Agency:
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R01 DE016680-07/DE/NIDCR NIH HHS; R01CA86839/CA/NCI NIH HHS; R01DE016680/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Immediate-Early Proteins; 0/Interferon Regulatory Factor-7; 0/ORF45 protein, Kaposi's sarcoma-associated herpesvirus |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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