Kaposi sarcoma-associated herpesvirus degrades cellular toll-interleukin-1 receptor domain-containing adaptor-inducing β-interferon (TRIF)

Humera Ahmad, Rachel Gubbels, Erica Ehlers, Florencia Meyer, Thomas Waterbury, Rongtuan Lin, Luwen Zhang

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing β-interferon (TRIF, also called TIR-domain-containing adaptor molecule-1 (TICAM-1)) is a signaling adaptor molecule that is critically involved in the Toll-like receptor 3 (TLR-3) and TLR-4 signaling pathways for type I interferon (IFN) production, a key component of innate immunity against microbial infection. In this report, we find a new mechanism by which RTA blocks innate immunity by targeting cellular TRIF. RTA specifically degrades TRIF by shortening the half-life of TRIF protein. This RTA-mediated degradation is at least partially mediated through the ubiquitin-proteasome pathway because proteasome inhibitors as well as knockdown of cellular ubiquitin expression alleviate the degradation. RTA may not directly interact with TRIF and may activate TRIF degradation indirectly through an unknown mediator(s). RTA targets multiple regions of TRIF and may use its ubiquitin ligase domain for the degradation. In addition, physiological levels of TRIF protein are down-regulated duringKSHVlytic replication when RTA is expressed. Finally, RTA down-regulates double-stranded RNA-initiated activation of TLR-3 pathway, in the absence of degradation of IFN regulatory factor 7 (IRF-7). Taken together, these data suggest that KSHV employs a novel mechanism to block the innate immunity by degrading TRIF protein. This work may contribute to our understandings on how KSHV evades host immunity for its survival in vivo.

Original languageEnglish (US)
Pages (from-to)7865-7872
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
StatePublished - Mar 11 2011

Fingerprint

Human Herpesvirus 8
Interleukin-1 Receptors
Transcription
Interferons
Ubiquitin
Innate Immunity
Toll-Like Receptor 3
Interferon Regulatory Factor-7
Degradation
Interferon Type I
Proteins
Proteasome Inhibitors
Double-Stranded RNA
Herpesviridae
Proteasome Endopeptidase Complex
Ligases
Half-Life
Immunity
Down-Regulation
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kaposi sarcoma-associated herpesvirus degrades cellular toll-interleukin-1 receptor domain-containing adaptor-inducing β-interferon (TRIF). / Ahmad, Humera; Gubbels, Rachel; Ehlers, Erica; Meyer, Florencia; Waterbury, Thomas; Lin, Rongtuan; Zhang, Luwen.

In: Journal of Biological Chemistry, Vol. 286, No. 10, 11.03.2011, p. 7865-7872.

Research output: Contribution to journalArticle

Ahmad, Humera ; Gubbels, Rachel ; Ehlers, Erica ; Meyer, Florencia ; Waterbury, Thomas ; Lin, Rongtuan ; Zhang, Luwen. / Kaposi sarcoma-associated herpesvirus degrades cellular toll-interleukin-1 receptor domain-containing adaptor-inducing β-interferon (TRIF). In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 10. pp. 7865-7872.
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AU - Zhang, Luwen

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AB - Kaposi sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing β-interferon (TRIF, also called TIR-domain-containing adaptor molecule-1 (TICAM-1)) is a signaling adaptor molecule that is critically involved in the Toll-like receptor 3 (TLR-3) and TLR-4 signaling pathways for type I interferon (IFN) production, a key component of innate immunity against microbial infection. In this report, we find a new mechanism by which RTA blocks innate immunity by targeting cellular TRIF. RTA specifically degrades TRIF by shortening the half-life of TRIF protein. This RTA-mediated degradation is at least partially mediated through the ubiquitin-proteasome pathway because proteasome inhibitors as well as knockdown of cellular ubiquitin expression alleviate the degradation. RTA may not directly interact with TRIF and may activate TRIF degradation indirectly through an unknown mediator(s). RTA targets multiple regions of TRIF and may use its ubiquitin ligase domain for the degradation. In addition, physiological levels of TRIF protein are down-regulated duringKSHVlytic replication when RTA is expressed. Finally, RTA down-regulates double-stranded RNA-initiated activation of TLR-3 pathway, in the absence of degradation of IFN regulatory factor 7 (IRF-7). Taken together, these data suggest that KSHV employs a novel mechanism to block the innate immunity by degrading TRIF protein. This work may contribute to our understandings on how KSHV evades host immunity for its survival in vivo.

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