Implication of TRIMalpha and TRIMCyp in interferon-induced anti-retroviral restriction activities

<p>Abstract</p> <p>Background</p> <p>TRIM5α is a restriction factor that interferes with retroviral infections in a species-specific manner in primate cells. Although TRIM5α is constitutively expressed, its expression has been shown to be up-regulated by type I interferon (IFN). Among primates, a particular case exists in owl monkey cells, which express a fusion protein between TRIM5 and cyclophilin A, TRIMCyp, specifically interfering with HIV-1 infection. No studies have been conducted so far concerning the possible induction of TRIMCyp by IFN. We investigated the consequences of IFN treatment on retroviral restriction in diverse primate cells and evaluated the implication of TRIM5α or TRIMCyp in IFN-induced anti-retroviral activities.</p> <p>Results</p> <p>First, we show that human type I IFN can enhance TRIM5α expression in human, African green monkey and macaque cells, as well as TRIMCyp expression in owl monkey cells. In TRIM5α-expressing primate cell lines, type I IFN has little or no effect on HIV-1 infection, whereas it potentates restriction activity against N-MLV in human and African green monkey cells. In contrast, type I IFN treatment of owl monkey cells induces a great enhancement of HIV-1 restriction, as well as a strain-tropism independent restriction of MLV. We were able to demonstrate that TRIM5α is the main mediator of the IFN-induced activity against N-MLV in human and African green monkey cells, whereas TRIMCyp mediates the IFN-induced HIV-1 restriction enhancement in owl monkey cells. In contrast, the type I IFN-induced anti-MLV restriction in owl monkey cells is independent of TRIMCyp expression.</p> <p>Conclusion</p> <p>Together, our observations indicate that both TRIM5α and TRIMCyp are implicated in IFN-induced anti-retroviral response in primate cells. Furthermore, we found that type I IFN also induces a TRIMCyp-independent restriction activity specific to MLV in owl monkey cells.</p

Interferon-beta induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells.

Interferon-β induces S phase slowing via up-regulated expression of PML in squamous carcinoma cell

De nouvelles perspectives thérapeutiques pour l’arsenic

Le traitement depuis 1996 de la leucémie aiguë promyélocytaire par le trioxyde d’arsenic (As2O3) a ouvert la voie de son utilisation dans d’autres cancers. Fait nouveau, l’As2O3 permet aussi de traiter les syndromes auto-immuns et lymphoprolifératifs de la souris MRL/lpr en induisant l’apoptose des lymphocytes T activés responsables des atteintes cutanées, pulmonaires et rénales, et de la lymphoprolifération. L’As2O3 normalise les taux sériques de nombreuses cytokines (TNF-α, IL-18, IFN-γ, IL-10), de Fas ligand, et des métabolites du monoxyde d’azote. En inhibant la production d’auto-anticorps, il bloque le développement de la glomérulonéphrite, ce qui conduit à une augmentation spectaculaire de la durée de vie de la souris

Les isoformes de PML et la réponse au TGF-β

PML (promyelocytic leukemia) est la protéine organisatrice des corps nucléaires, une structure multiprotéique associée à la matrice nucléaire, impliquée dans différents processus cellulaires. Sept isoformes principales de PML, dont six nucléaires (PMLI à VI) et une cytoplasmique (PMLVII), sont générées par épissage alternatif d’un gène unique. D’une part, PML dans le cytoplasme régule positivement le signal de transduction donné par le TGF-β, en augmentant la phosphorylation des facteurs de transcription SMAD2/3 et, d’autre part, PML augmente dans le noyau l’activation de la caspase 8 et l’apoptose en réponse au TGF-β. L’absence de PML rend les cellules résistantes à l’apoptose induite par le TGF-β. Dans le noyau, PML est localisée majoritairement dans le nucléoplasme, une petite fraction étant cependant retrouvée dans la matrice nucléaire. Le TGF-β cible PML dans le noyau en induisant sa conjugaison à SUMO (small ubiquitin modifier), son transfert et celui de la caspase 8 vers la matrice nucléaire où les deux protéines se localisent au sein des corps nucléaires PML. Cette revue rend compte des implications de PML dans le cytoplasme et le noyau dans la réponse au TGF-β

The Nucleocytoplasmic Rabies Virus P Protein Counteracts Interferon Signaling by Inhibiting both Nuclear Accumulation and DNA Binding of STAT1

Rabies virus P protein inhibits alpha interferon (IFN-α)- and IFN-γ-stimulated Jak-STAT signaling by retaining phosphorylated STAT1 in the cytoplasm. Here, we show that P also blocks an intranuclear step that is the STAT1 binding to the DNA promoter of IFN-responsive genes. As P is a nucleocytoplasmic shuttling protein, we first investigated the effect of the cellular distribution of P on the localization of STAT1 and consequently on IFN signaling. We show that the localization of STAT1 is correlated with the localization of P: in cells expressing a nuclear form of P (the short P3 isoform or the complete P in the presence of the export inhibitor leptomycin B), STAT1 is nuclear, whereas in cells expressing a cytoplasmic form of P, STAT1 is cytoplasmic. However, the expression of nuclear forms of P inhibits the signaling of both IFN-γ and IFN-α, demonstrating that the retention of STAT1 in the cytoplasm is not the only mechanism involved in the inhibition of IFN signaling. Electrophoretic mobility shift analysis indicates that P expression in the cell extracts of infected cells or in stable cell lines prevents IFN-induced DNA binding of STAT1. The loss of the DNA binding of STAT1 and ISGF3 was also observed when purified recombinant P or P3 was added to the extracts of IFN-γ- or IFN-α-treated cells, indicating that P directly affects the DNA binding activity of STAT1. Then products of the rabies virus P gene are able to counteract IFN signaling by creating both cytoplasmic and nuclear blocks for STAT1

Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies.

Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative, and immunomodulatory activities. The different biologic actions of IFN are believed to be mediated by the products of specifically IFN-stimulated genes (ISG) in the target cells. The IFN response is the first line of defense against viral infections. Viruses, which require the cellular machinery for their replication, have evolved different ways to counteract the action of IFN by inhibiting IFN production or Jak-Stat signaling or by altering ISG products. This review focuses on the role of viral proteins from the RNA virus family, particularly rabies P protein. P protein mediates inhibition of the IFN system by different pathways: it inhibits IFN production by impairing IFN regulatory factor-3 (IRF-3) phosphorylation and IFN signaling by blocking nuclear transport of Stat1 and alters promyelocytic leukemia (PML) nuclear bodies by retaining PML in the cytoplasm