Nuclear Translocation and Activation of the Transcription Factor NFAT Is Blocked by Herpes Simplex Virus Infection

Abstract

Transcription factors of the NFAT (nuclear factor of activated T cells) family are expressed in most immune system cells and in a range of other cell types. Signaling through NFAT is implicated in the regulation of transcription for the immune response and other processes, including differentiation and apoptosis. NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation pathway is the regulation of its nuclear import by the Ca 2؉ /calmodulin-dependent phosphatase calcineurin. In a cell line stably expressing green fluorescent protein (GFP)-NFAT, this import can be triggered by elevation of intracellular calcium and visualized in live cells. Here we show that the inducible nuclear import of GFP-NFAT is efficiently blocked at early stages of herpes simplex virus (HSV) infection. This is a specific effect, since we observed abundant nuclear accumulation of a test viral protein and no impediment to general nuclear localization signaldependent nuclear import and retention in infected cells. We show that virus binding at the cell surface is not itself sufficient to inhibit the signaling that induces NFAT nuclear translocation. Since the block occurs following infection in the presence of phosphonoacetic acid but not cycloheximide, we infer that the entry of the virion and early gene transcription are required but the effect is independent of DNA replication or late virus gene expression. A consequence of the block to GFP-NFAT import is a reduction in NFAT-dependent transcriptional activation from the interleukin-2 promoter in infected cells. This HSV-mediated repression of the NFAT pathway may constitute an immune evasion strategy or subversion of other NFAT-dependent cellular processes to promote viral replication.Herpesviruses subvert a range of host cellular processes by interference with signal transduction pathways. For example, mitogenic kinase cascades are activated to establish a cellular environment favorable for virus replication (19,33). Apoptotic pathways are repressed during infection to prevent cell death prior to virus release and possibly also to protect latently infected neuronal cells from destruction (9,24,30). Furthermore, to help evade host immune detection, infection disrupts cytokine-mediated signaling networks crucial for cell-mediated immunity (14), and apoptosis is induced in activated T lymphocytes and macrophages (16,46,54).A key aspect of the regulated transcription response to immune stimuli is the Ca 2ϩ /calmodulin-dependent signal cascade which leads to the activation of the NFAT (nuclear factor of activated T cells) family of transcription factors (51). The family encompasses four closely related proteins, NFAT1 to -4, which share structural and functional homology and are expressed in numerous cell types of the immune system as well as in a range of other cells, including muscle, cardiac, and neuronal cells (7,20,37). These proteins have a conserved Nterminal transactivation domain and a central DNA binding domain with homology to the DNA binding domains of Rel/ ...

Human X‐DING‐CD4 mediates resistance to HIV‐1 infection through novel paracrine‐like signaling

“…(IV) motif is found in yeast and vertebrates [52][53][54][55] and is required for targeting of CN substrates. We suggest that CN facilitates the X-DING nuclear translocation, as was shown for another transcription regulator, NFAT [56,57], and further studies will clarify the role of this motif in the formation of the X-DING/CN complex and the nuclear translocation of this protein. Interruption of the calcineurin pathway by cyclosporine A also interrupted X-DING activity, thus confirming the importance of CN in the X-DING mechanism (M. Simm, unpublished data).…”

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

“…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.…”

Varicella-Zoster Virus Infection Influences Expression and Organization of Actin and α-Tubulin but Does Not Affect Lamin A and Vimentin

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