A Viral Mechanism for Inhibition of the Cellular Phosphatase Calcineurin

Miskin, James; Abrams, Charles C.; Goatley, Lynnette; Dixon, Linda K.

doi:10.1126/science.281.5376.562

Cited by 134 publications

(114 citation statements)

References 21 publications

(6 reference statements)

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“…Inhibition of calcineurin phosphatase activity by A238L in ASFV-infected macrophages and Vero cells has been previously described (7). To study the effect of this inhibition in the control of NFAT by A238L, those authors cotransfected RS-2 cells with a vector expressing A238L along with an NFAT-dependent reporter gene.…”

Section: Discussionmentioning

confidence: 99%

“…A238L has been previously involved in decreasing calcineurin activity both in ASFV-infected alveolar macrophages and Vero cells (7). To investigate the involvement of the calcineurin NFAT pathway in the A238L-mediated modulation of COX-2, we transiently cotransfected NFAT or calcineurin expressing plasmids together with the P2-1900 construct that contains the full-length sequence of the COX-2 promoter, into Jurkat-pcDNA or Jurkat-A238L cells.…”

Section: Nfat and Calcineurin But Not P65 Participate In The Transcmentioning

confidence: 99%

“…Functionally, the viral protein prevents translocation and binding of p65-p50 NF B dimers to their target sequence in the DNA (6). It has been described that A238L is also able to inhibit NFAT activation by inhibiting the calcineurin phosphatase activity (7). Therefore, the special features of this viral I B homologue would enable the virus to act on both NF B-and NFAT-dependent pathways, probably modulating the expression of genes involved in the development of a protective immune response against the virus (24).…”

mentioning

confidence: 99%

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The Viral Protein A238L Inhibits Cyclooxygenase-2 Expression through a Nuclear Factor of Activated T Cell-dependent Transactivation Pathway

Granja

Nogal

Hurtado

et al. 2004

Journal of Biological Chemistry

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Cyclooxygenase-2 is transiently induced upon cell activation or viral infections, resulting in inflammation and modulation of the immune response. 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. Transfection of Jurkat cells stably expressing A238L with cyclooxygenase-2 promoter-luciferase constructs containing 5 -terminal deletions or mutations in distal or proximal nuclear factor of activated T cell (NFAT) response elements revealed that these sequences are involved in the inhibition induced by A238L. Overexpression of a constitutively active version of the calciumdependent phosphatase calcineurin or NFAT reversed the inhibition mediated by A238L on cyclooxygenase-2 promoter activation, whereas overexpression of p65 NF B had no effect. A238L does not modify the nuclear localization of NFAT after phorbol 12-myristate 13-acetate/calcium ionophore stimulation. Moreover, we show that the mechanism by which the viral protein downregulates cyclooxygenase-2 activity does not involve inhibition of the binding between NFAT and its specific DNA sequences into the cyclooxygenase-2 promoter. Strikingly, A238L dramatically inhibited the transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFAT1. Taken together, these data indicate that A238L down-regulates cyclooxygenase-2 transcription through the NFAT response elements, being NFAT-dependent transactivation implicated in this down-regulation.Viruses have been known for a long time to use a variety of strategies not only to alter the host metabolism via their signaling proteins but also to hijack cellular signaling pathways and transcription factors to control them to their own advantage. Both the nuclear factor-B (NF B) 1 and the nuclear factor of activated T cells (NFAT) pathways appear to be attractive targets for common viral pathogens, probably due to their ability to promote the expression of numerous proteins involved in adaptative and innate immunity (1, 2). Several viruses, including hepatitis C virus (3), immunodeficiency virus (4), herpes viruses (5), and African swine fever virus (ASFV) (6 -8) have been shown to modulate the activation of NFAT or NF B.NF B is a collective term referring to a class of dimeric transcription factors belonging to the rel family. In resting cells, NF B exists in the cytoplasm as an inactive complex bound to inhibitory proteins of the I B family (9, 10). In response to a variety of stimuli, I B proteins undergo phosphorylation of Ser 32 and Ser 36 (11, 12), followed by ubiquitination and degradation in the proteasome, thus unmasking the nuclear localization sequence of the transactivating heterodimers and allowing translocation of active NF B to the nucleus. Recently, there is accumulating evidence suggesting that another level of NF-〉 regulation independent on I B degradation exists. This second level of regulation relies in the activation of the transcription...

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Section: Discussionmentioning

confidence: 99%

Section: Nfat and Calcineurin But Not P65 Participate In The Transcmentioning

confidence: 99%

mentioning

confidence: 99%

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The Viral Protein A238L Inhibits Cyclooxygenase-2 Expression through a Nuclear Factor of Activated T Cell-dependent Transactivation Pathway

Granja

Nogal

Hurtado

et al. 2004

Journal of Biological Chemistry

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“…Of these, a few have been identified as role players in the evasion of the host defense mechanism. Viral protein A238L (5EL) inhibits host NF k B and calcineurin (Powell et al, 1996;Miskin et al, 1998;Revilla et al, 1998). The transcriptional activation in infected macrophages of genes dependent on NF k B is inhibited as a result, and so is the activation of the nuclear factor of activated T cells (NFAT) transcription factor family regulated by calcineurin.…”

Section: Proteinsmentioning

confidence: 99%

“…The transcriptional activation in infected macrophages of genes dependent on NF k B is inhibited as a result, and so is the activation of the nuclear factor of activated T cells (NFAT) transcription factor family regulated by calcineurin. Virus protein 5EL evades and modulates or interferes with the host immune response, including suppression of immune responses in vitro (Powell et al, 1996;Miskin et al, 1998). The 8DR protein, also called CD2v, is a virus adhesion protein involved in virus spread and impairment of lymphocyte function (Borca et al, 1998;Tulman and Rock, 2001;Dixon et al, 2004).…”

Section: Proteinsmentioning

confidence: 99%