Mechanism of inactivation of NF-κΒ by a viral homologue of ΙκΒα. Signal-induced release of ΙκΒα results in the binding of the viral homologue to NF-κΒ

Tait, S.W.G. (2000) Mechanism of inactivation of NF-κΒ by a viral homologue of ΙκΒα. Signal-induced release of ΙκΒα results in the binding of the viral homologue to NF-κΒ. Journal of Biological Chemistry, 275(44), pp. 34656-34664. (doi: 10.1074/jbc.M000320200)

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Publisher's URL: http://dx.doi.org/10.1074/jbc.M000320200

Abstract

Activation of the nuclear factor κB plays a key role in viral pathogenesis, resulting in inflammation and modulation of the immune response. We have previously shown that A238L, an open reading frame from African swine fever virus (ASFV), encoding a protein with 40% homology to porcine IκBα exerts a potent anti-inflammatory effect in host macrophages, where it down-regulates NF-κB-dependent gene transcription and proinflammatory cytokine production. This paper reveals the mechanism of suppression of NF-κB activity by A238Lp. A238Lp is synthesized throughout infection as two molecular mass forms of 28 and 32 kDa, and vaccinia-mediated expression of A238L demonstrated that both proteins are produced from a single gene. Significantly, the higher 32-kDa form of A238L, but not the 28-kDa form, interacts directly with RelA, the 65-kDa subunit of NF-κB, indicating that the binding is dependent on a post-translational modification. Immunoprecipitation analysis shows the NF-κB p65-A238L p32 heterodimer is a separate complex from NF-κB-IκBα, and it resides in the cytoplasm. Moreover, we show that ASFV infection stimulates the NFκB signal transduction pathway, which results in the rapid degradation of endogenous IκBα, although both forms of A238Lp are resistant to stimulus-induced degradation. Using the proteasome inhibitor MG132, we show that when degradation of IκBα is inhibited, A238Lp binding to NF-κB p65 is reduced. The results suggest that the virus exploits its activation of the NF-κB pathway to enable its own IκB homologue to bind to NF-κB p65. Last, we show that synthesis of IκBα is increased during ASFV infection, indicating RelA-independent transcription of the IκBα gene.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen
Authors: Tait, S.W.G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:08 August 2000

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