| Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation. | |
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MedLine Citation:
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PMID: 22130545 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. As obligate pathogens, gammaherpesviruses have evolved a plethora of mechanisms to evade host immune responses. We have previously shown that murine gammaherpesvirus 68 (γHV68) induces the degradation of RelA, an essential subunit of the transcriptionally active NF-κB dimer, to evade cytokine production. Here, we report that the immediately early gene product of γHV68, replication transactivator (RTA), functions as a ubiquitin E3 ligase to promote RelA degradation and abrogate cytokine production. A targeted genomic screen identified that RTA, out of 24 candidates, induces RelA degradation and abolishes NF-κB activation. Biochemical analyses indicated that RTA interacts with RelA and promotes RelA ubiquitination, thereby facilitating RelA degradation. Mutations within a conserved cysteine/histidine-rich, putative E3 ligase domain impaired the ability of RTA to induce RelA ubiquitination and degradation. Moreover, infection by recombinant γHV68 carrying mutations that diminish the E3 ligase activity of RTA resulted in more robust NF-κB activation and cytokine induction than did infection by wild-type γHV68. These findings support the conclusion that γHV68 subverts early NF-κB activation and cytokine production through RTA-induced RelA degradation, uncovering a key function of RTA that antagonizes the intrinsic cytokine production during gammaherpesvirus infection. |
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Authors:
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Xiaonan Dong; Zhiheng He; Deniz Durakoglugil; Lisa Arneson; Yan Shen; Pinghui Feng |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-11-30 |
Journal Detail:
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Title: Journal of virology Volume: 86 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-01-27 Completed Date: 2012-03-19 Revised Date: 2012-03-28 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 1930-41 Citation Subset: IM |
Affiliation:
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Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cytokines / immunology* Female Herpesviridae Infections / immunology, metabolism, veterinary*, virology Humans Immediate-Early Proteins / genetics, immunology, metabolism* Immune Evasion* Male Mice Mice, Inbred C57BL Protein Binding Rhadinovirus / genetics, immunology*, physiology Rodent Diseases / immunology*, metabolism, virology Transcription Factor RelA / genetics, immunology, metabolism* Viral Proteins / genetics, immunology, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DE021445/DE/NIDCR NIH HHS; R01 CA134241/CA/NCI NIH HHS; R01 CA134241-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Immediate-Early Proteins; 0/Rela protein, mouse; 0/Transcription Factor RelA; 0/Viral Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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