Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation

Xiaonan Dong, Zhiheng He, Deniz Durakoglugil, Lisa Arneson, Yan Shen, Pinghui Feng

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1930-1941
Number of pages12
JournalJournal of Virology
Volume86
Issue number4
DOIs
StatePublished - Feb 2012

Fingerprint

Murid herpesvirus 4
Trans-Activators
cytokines
Cytokines
degradation
Ubiquitin-Protein Ligases
Ubiquitination
ligases
Infection
infection
mutation
Mutation
ubiquitin-protein ligase
pathogens
transactivators
histidine
Histidine
Cysteine
cysteine
immune response

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation. / Dong, Xiaonan; He, Zhiheng; Durakoglugil, Deniz; Arneson, Lisa; Shen, Yan; Feng, Pinghui.

In: Journal of Virology, Vol. 86, No. 4, 02.2012, p. 1930-1941.

Research output: Contribution to journalArticle

Dong, Xiaonan ; He, Zhiheng ; Durakoglugil, Deniz ; Arneson, Lisa ; Shen, Yan ; Feng, Pinghui. / Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation. In: Journal of Virology. 2012 ; Vol. 86, No. 4. pp. 1930-1941.
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