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The MC160 protein expressed by the dermatotropic poxvirus molluscum contagiosum virus prevents tumor necrosis factor alpha-induced NF-kappaB activation via inhibition of I kappa kinase complex formation.

Abstract：

:The pluripotent cytokine tumor necrosis factor alpha (TNF-alpha) binds to its cognate TNF receptor I (TNF-RI) to stimulate inflammation via activation of the NF-kappaB transcription factor. To prevent the detrimental effects of TNF-alpha in keratinocytes infected with the molluscum contagiosum virus (MCV), this poxvirus is expected to produce proteins that block at least one step of the TNF-RI signal transduction pathway. One such product, the MC160 protein, is predicted to interfere with this cellular response because of its homology to other proteins that regulate TNF-RI-mediated signaling. We report here that expression of MC160 molecules did significantly reduce TNF-alpha-mediated NF-kappaB activation in 293T cells, as measured by gene reporter and gel mobility shift assays. Since we observed that MC160 decreased other NF-kappaB activation pathways, namely those activated by receptor-interacting protein, TNF receptor-associated factor 2, NF-kappaB-inducing kinase, or MyD88, we hypothesized that the MC160 product interfered with I kappa kinase (IKK) activation, an event common to multiple signal transduction pathways. Indeed, MC160 protein expression was associated with a reduction in in vitro IKK kinase activity and IKK subunit phosphorylation. Further, IKK1-IKK2 interactions were not detected in MC160-expressing cells, under conditions demonstrated to induce IKK complex formation, but interactions between the MC160 protein and the major IKK subunits were undetectable. Surprisingly, MC160 expression correlated with a decrease in IKK1, but not IKK2 levels, suggesting a mechanism for MC160 disruption of IKK1-IKK2 interactions. MCV has probably retained its MC160 gene to inhibit NF-kappaB activation by interfering with signaling via multiple biological mediators. In the context of an MCV infection in vivo, MC160 protein expression may dampen the cellular production of proinflammatory molecules and enhance persistent infections in host keratinocytes.

journal_name

J Virol

journal_title

Journal of virology

authors

Nichols DB,Shisler JL

doi

10.1128/JVI.80.2.578-586.2006

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

578-86

issue

eissn

0022-538X

issn

1098-5514

pii

80/2/578

journal_volume

pub_type

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The MC160 protein expressed by the dermatotropic poxvirus molluscum contagiosum virus prevents tumor necrosis factor alpha-induced NF-kappaB activation via inhibition of I kappa kinase complex formation.