The MCV MC159 protein inhibits late, but not early, events of TNF-α-induced NF-κB activation

Lyre Espada Murao, Joanna L. Shisler

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor necrosis factor (TNF-α) triggers biphasic activation of the NF-κB transcriptional regulator. This process consists of an initial, IκBα-mediated transient phase and a later, persistent phase dependent on IκBβ degradation. To presumably interfere with the fulfillment of this immunity-associated event in cells infected with the molluscum contagiosum virus (MCV), this pathogen produces the intracellular MC159 protein. To define the mode of action of MC159, the impact of TNF-α on HEK 293T cells ectopically expressing the MC159 protein was examined. In this regard, TNF-α-induced expression of an NF-κB-regulated luciferase reporter gene was partially inhibited by the MC159 protein. This ability was attributed to blockage of the persistent phase of TNF-α-induced NF-κB activation for the following reasons: (1) the initial phase of NF-κB transcriptional activation was not affected by the MC159 protein; (2) the MC159 protein inhibited TNF-α-directed degradation of IκBβ, but not IκBα; and (3) expression of the late NF-κB-regulated cell genes, TNF-α and CCL2, was decreased in the presence of the MC159 protein while transcription of the early NF-κB-regulated cell gene, CXCL1, was not altered. Previously reported MC159-RIP interactions appear to be irrelevant for the MC159 inhibitory function. In contrast, MC159-TRAF2 associations are more relevant for inhibitory function since mutant MC159 proteins unable to bind TRAF2 also cannot inhibit TNF-mediated NF-κB activation. In vivo, the MC159 protein may act to prolong virus survival by preventing the infected cell from responding to TNF-α, ultimately preventing the cellular production of proinflammatory and immunoattractant molecules.

Original languageEnglish (US)
Pages (from-to)255-264
Number of pages10
JournalVirology
Volume340
Issue number2
DOIs
StatePublished - Sep 30 2005

Keywords

  • IκBα
  • IκBβ
  • MC159
  • MCV
  • NF-κB
  • RIP
  • TNF-α
  • TRAF2
  • v-FLIP

ASJC Scopus subject areas

  • Virology

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