PMID:22301546

Citation	Randall, CM, Jokela, JA and Shisler, JL (2012) The MC159 protein from the molluscum contagiosum poxvirus inhibits NF-κB activation by interacting with the IκB kinase complex. J. Immunol. 188:2371-9
Abstract	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.
Links	PubMed PMC3288875 Online version:10.4049/jimmunol.1100136
Keywords	Animals; Cell Communication/immunology; HEK293 Cells; Humans; I-kappa B Kinase/metabolism; I-kappa B Kinase/physiology; Mice; Molluscum Contagiosum/enzymology; Molluscum Contagiosum/immunology; Molluscum Contagiosum/metabolism; Molluscum contagiosum virus/immunology; NF-kappa B/antagonists & inhibitors; NF-kappa B/metabolism; NF-kappa B/physiology; Viral Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MCV1:CFLA		GO:0039504: suppression by virus of host adaptive immune response	ECO:0000314:		P		As seen in figure 8, the MC159 protein interacts with IKKγ during poxvirus infection. The IKK complex plays a crucial role in NF-κB activation, making it an appealing target for poxviruses as a means to block NF-κB-mediated activation of the pro-inflammatory response.	complete CACAO 6885

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