TLR-TRIF pathway enhances the expression of KSHV replication and transcription activator

Florencia Meyer, Erica Ehlers, Andrew Steadman, Thomas Waterbury, Mingxia Cao, Luwen Zhang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus. KSHV replication and transcription activator (RTA) is necessary and sufficient for KSHV reactivation from latency. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, act through adaptors, and initiate innate and adaptiveimmuneresponses against pathogens. Toll/interleukin-1-receptor domain containing adaptor protein inducing interfer-on-β (TRIF) is an adaptor associated with TLR3 and TLR4 signaling, and is closely related to antiviral signaling to activate type I interferon (IFN) production. We previously found that KSHV RTA degrades TRIF indirectly and blocks TLR3 pathways. In this report, wefind that TRIF, as well as TLR3 activation, enhances KSHV RTA protein expression. The C-terminal region of the RTA is involved in the responding TRIF-mediated enhancement. The degradation of TRIF and the enhancement of RTA expression are using two different pathways. The enhancement by TLR-TRIF is at least partially via promoting translational efficiency of RTA mRNA. Finally, the receptor-interacting protein 1 (RIP1) may be involved in TRIF-mediated enhancement of RTA expression, but not in the RTA-mediated degradation of TRIF. Therefore, the activation of TLR-TRIF pathway enhances KSHV RTA protein expression, and KSHV RTA in turn degrades TRIF to block innate immunity. The putative KSHV-TLR-adaptor-interacting loopmaybea critical element to evade and usurp host innate immunity in KSHV life-cycle.

Original languageEnglish (US)
Pages (from-to)20435-20442
Number of pages8
JournalJournal of Biological Chemistry
Volume288
Issue number28
DOIs
StatePublished - Jul 12 2013

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Human Herpesvirus 8
Toll-Like Receptors
Transcription
Innate Immunity
Receptor-Interacting Protein Serine-Threonine Kinases
Chemical activation
Interferon Type I
Proteins
Interleukin-1 Receptors
Degradation
Herpesviridae
Life Cycle Stages
Pathogens
Antiviral Agents
Life cycle
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

TLR-TRIF pathway enhances the expression of KSHV replication and transcription activator. / Meyer, Florencia; Ehlers, Erica; Steadman, Andrew; Waterbury, Thomas; Cao, Mingxia; Zhang, Luwen.

In: Journal of Biological Chemistry, Vol. 288, No. 28, 12.07.2013, p. 20435-20442.

Research output: Contribution to journalArticle

Meyer, Florencia ; Ehlers, Erica ; Steadman, Andrew ; Waterbury, Thomas ; Cao, Mingxia ; Zhang, Luwen. / TLR-TRIF pathway enhances the expression of KSHV replication and transcription activator. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 28. pp. 20435-20442.
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AU - Ehlers, Erica

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AU - Zhang, Luwen

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AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus. KSHV replication and transcription activator (RTA) is necessary and sufficient for KSHV reactivation from latency. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, act through adaptors, and initiate innate and adaptiveimmuneresponses against pathogens. Toll/interleukin-1-receptor domain containing adaptor protein inducing interfer-on-β (TRIF) is an adaptor associated with TLR3 and TLR4 signaling, and is closely related to antiviral signaling to activate type I interferon (IFN) production. We previously found that KSHV RTA degrades TRIF indirectly and blocks TLR3 pathways. In this report, wefind that TRIF, as well as TLR3 activation, enhances KSHV RTA protein expression. The C-terminal region of the RTA is involved in the responding TRIF-mediated enhancement. The degradation of TRIF and the enhancement of RTA expression are using two different pathways. The enhancement by TLR-TRIF is at least partially via promoting translational efficiency of RTA mRNA. Finally, the receptor-interacting protein 1 (RIP1) may be involved in TRIF-mediated enhancement of RTA expression, but not in the RTA-mediated degradation of TRIF. Therefore, the activation of TLR-TRIF pathway enhances KSHV RTA protein expression, and KSHV RTA in turn degrades TRIF to block innate immunity. The putative KSHV-TLR-adaptor-interacting loopmaybea critical element to evade and usurp host innate immunity in KSHV life-cycle.

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