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Gene Review:

A238L - IkB-like protein

African swine fever virus

Tait, S.W. et al., Powell, P.P. et al., Miskin, J.E. et al., Granja, A.G. et al., Lautermilch, N.J. et al., et al.

Powell, Dixon, Parkhouse, Lautermilch, Spitzer,

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Disease relevance of A238L

African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT [1].

High impact information on A238L

African swine fever virus (ASFV) is able to inhibit TNF-alpha-induced gene expression through the synthesis of A238L protein [2].
In addition, we show that A238L is a nuclear protein that binds to the cyclic AMP-responsive element/kappa3 complex, thus displacing the CREB binding protein/p300 coactivators [2].
Here we report that A238L, an African swine fever virus protein, efficiently inhibits cyclooxygenase-2 gene expression in Jurkat T cells and in virus-infected Vero cells [3].
We have previously shown that A238L, an open reading frame from African swine fever virus (ASFV), encoding a protein with 40% homology to porcine I kappa B alpha exerts a potent anti-inflammatory effect in host macrophages, where it down-regulates NF-kappa B-dependent gene transcription and proinflammatory cytokine production [4].
Significantly, the higher 32-kDa form of A238L, but not the 28-kDa form, interacts directly with RelA, the 65-kDa subunit of NF-kappa B, indicating that the binding is dependent on a post-translational modification [4].

Chemical compound and disease context of A238L

Pharmacological blockers of CN (cyclosporin A and deltamethrin) and peptide inhibitors of CN [the Xenopus CN (xCN) autoinhibitory domain and African swine fever virus protein A238L] block the Ca(2+)-dependent reduction of neurite outgrowth in cultured neurons [5].

Biological context of A238L

Although A238L-mediated suppression of NF-kappaB-dependent gene expression occurs by a different mechanism, the A238L-calcineurin interaction may be required to stabilize A238L [1].
By using a recombinant ASFV from which the A238L gene had been deleted, it was shown that expression of A238L did not inhibit nuclear import of the NF-kappaB p50 or p65 subunit and did not inhibit nuclear export of p65 by a CRM1-mediated pathway [6].
Finally, A238L abrogated p300 transactivation mediated by a GAL4-p300 construction [7].
An interleukin-8 promoter, containing an NFkappaB enhancer site, driving expression of a luciferase reporter gene was used to show that NFkappaB-dependent transcription was inhibited by the virus and by a cloned ASFV gene, A238L [8].
Expression at mRNA level of cytokines and A238L gene in porcine blood-derived macrophages infected in vitro with African swine fever virus (ASFV) isolates of different virulence [9].

Analytical, diagnostic and therapeutic context of A238L

Electrophoretic mobility shift assay showed that cells expressing the A238L gene inhibited NFkappaB binding to DNA [8].

References

African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT. Miskin, J.E., Abrams, C.C., Dixon, L.K. J. Virol. (2000) [Pubmed]
The viral protein A238L inhibits TNF-alpha expression through a CBP/p300 transcriptional coactivators pathway. Granja, A.G., Nogal, M.L., Hurtado, C., Del Aguila, C., Carrascosa, A.L., Salas, M.L., Fresno, M., Revilla, Y. J. Immunol. (2006) [Pubmed]
The viral protein A238L inhibits cyclooxygenase-2 expression through a nuclear factor of activated T cell-dependent transactivation pathway. Granja, A.G., Nogal, M.L., Hurtado, C., Vila, V., Carrascosa, A.L., Salas, M.L., Fresno, M., Revilla, Y. J. Biol. Chem. (2004) [Pubmed]
Mechanism of inactivation of NF-kappa B by a viral homologue of I kappa b alpha. Signal-induced release of i kappa b alpha results in binding of the viral homologue to NF-kappa B. Tait, S.W., Reid, E.B., Greaves, D.R., Wileman, T.E., Powell, P.P. J. Biol. Chem. (2000) [Pubmed]
Regulation of calcineurin by growth cone calcium waves controls neurite extension. Lautermilch, N.J., Spitzer, N.C. J. Neurosci. (2000) [Pubmed]
African swine fever virus A238L inhibitor of NF-{kappa}B and of calcineurin phosphatase is imported actively into the nucleus and exported by a CRM1-mediated pathway. Silk, R.N., Bowick, G.C., Abrams, C.C., Dixon, L.K. J. Gen. Virol. (2007) [Pubmed]
Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L-Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation. Granja, A.G., Sabina, P., Salas, M.L., Fresno, M., Revilla, Y. J. Virol. (2006) [Pubmed]
An IkappaB homolog encoded by African swine fever virus provides a novel mechanism for downregulation of proinflammatory cytokine responses in host macrophages. Powell, P.P., Dixon, L.K., Parkhouse, R.M. J. Virol. (1996) [Pubmed]
Expression at mRNA level of cytokines and A238L gene in porcine blood-derived macrophages infected in vitro with African swine fever virus (ASFV) isolates of different virulence. Gil, S., Spagnuolo-Weaver, M., Canals, A., Sepúlveda, N., Oliveira, J., Aleixo, A., Allan, G., Leitão, A., Martins, C.L. Arch. Virol. (2003) [Pubmed]

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