Molluscum contagiosum virus (MCV) causes persistent neoplasms in healthy and 
immunocompromised people. Its ability to persist likely is due to its arsenal of 
viral immunoevasion proteins. For example, the MCV MC159 protein inhibits 
TNF-R1-induced NF-κB activation and apoptosis. The MC159 protein is a viral FLIP 
and, as such, possesses two tandem death effector domains (DEDs). We show in 
this article that, in human embryonic kidney 293 T cells, the expression of 
wild-type MC159 or a mutant MC159 protein containing the first DED (MC159 A) 
inhibited TNF-induced NF-κB, or NF-κB activated by PMA or MyD88 overexpression, 
whereas a mutant protein lacking the first DED (MC159 B) did not. We 
hypothesized that the MC159 protein targeted the IκB kinase (IKK) complex to 
inhibit these diverse signaling events. Indeed, the MC159 protein, but not MC159 
B, coimmunoprecipitated with IKKγ. MC159 coimmunoprecipitated with IKKγ when 
using mouse embryonic fibroblasts that lack either IKKα or IKKβ, suggesting that 
the MC159 protein interacted directly with IKKγ. MC159-IKKγ 
coimmunoprecipitations were detected during infection of cells with either MCV 
isolated from human lesions or with a recombinant MC159-expressing vaccinia 
virus. MC159 also interacts with TRAF2, a signaling molecule involved in NF-κB 
activation. However, mutational analysis of MC159 failed to reveal a correlation 
between MC159-TRAF2 interactions and MC159's inhibitory function. We propose 
that MC159-IKK interactions, but not MC159-TRAF2 interactions, are responsible 
for inhibiting NF-κB activation.