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

Tumor necrosis factor (TNF-alpha) triggers biphasic activation of the NF-kappaB transcriptional regulator. This process consists of an initial, IkappaBalpha-mediated transient phase and a later, persistent phase dependent on IkappaBbeta 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-alpha on HEK 293T cells ectopically expressing the MC159 protein was examined. In this regard, TNF-alpha-induced expression of an NF-kappaB-regulated luciferase reporter gene was partially inhibited by the MC159 protein. This ability was attributed to blockage of the persistent phase of TNF-alpha-induced NF-kappaB activation for the following reasons: (1) the initial phase of NF-kappaB transcriptional activation was not affected by the MC159 protein; (2) the MC159 protein inhibited TNF-alpha-directed degradation of IkappaBbeta, but not IkappaBalpha; and (3) expression of the late NF-kappaB-regulated cell genes, TNF-alpha and CCL2, was decreased in the presence of the MC159 protein while transcription of the early NF-kappaB-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-kappaB activation. In vivo, the MC159 protein may act to prolong virus survival by preventing the infected cell from responding to TNF-alpha, ultimately preventing the cellular production of proinflammatory and immunoattractant molecules.