The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6.

in Oncogene (2011)

Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role ... [more ▼]

Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role in T-cell transformation. In response to stressful stimuli, cells mount a cellular stress response to limit the damage that environmental forces inflict on DNA or proteins. During stress response, cells postpone the translation of most cellular mRNAs, which are gathered into cytoplasmic mRNA-silencing foci called stress granules (SGs) and allocate their available resources towards the production of dedicated stress-management proteins. Here we demonstrate that Tax controls the formation of SGs and interferes with the cellular stress response pathway. In agreement with previous reports, we observed that Tax relocates from the nucleus to the cytoplasm in response to environmental stress. We found that the presence of Tax in the cytoplasm of stressed cells prevents the formation of SGs and counteracts the shutoff of specific host proteins. Unexpectedly, nuclear localization of Tax promotes spontaneous aggregation of SGs, even in the absence of stress. Mutant analysis revealed that the SG inhibitory capacity of Tax is independent of its transcriptional abilities but relies on its interaction with histone deacetylase 6, a critical component of SGs. Importantly, the stress-protective effect of Tax was also observed in the context of HTLV-1 infected cells, which were shown to be less prone to form SGs and undergo apoptosis under arsenite exposure. These observations identify Tax as the first virally encoded inhibitory component of SGs and unravel a new strategy developed by HTLV-1 to deregulate normal cell processes. We postulate that inhibition of the stress response pathway by Tax would favor cell survival under stressful conditions and may have an important role in HTLV-1-induced cellular transformation.Oncogene advance online publication, 2 May 2011; doi:10.1038/onc.2011.120. [less ▲]

Recent insights into Protein Phosphatase 2A structure and regulation : The reason why PP2A is no longer considered as a lazy passive housekeeping enzyme

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (2010), 14(1), 243-252

Reversible protein phosphorylation is a major intracellular mechanism for controlling many important physiological activities. In the past, most of the attention was focused primarily on protein kinases ... [more ▼]

Reversible protein phosphorylation is a major intracellular mechanism for controlling many important physiological activities. In the past, most of the attention was focused primarily on protein kinases and on their regulation, mainly because phosphatases were then viewed as simple housekeeping enzymes. But advances in the understanding of phosphatases make now clear that protein phosphatases are dynamic and highly regulated enzymes and are as important as kinases in the regulation of cellular processes involving protein phosphorylation. Protein phosphatase 2A (PP2A) is a very abundant -it accounts for as much as 1% of total cellular protein-, ubiquitous and remarkably conserved enzyme. By dephosphorylating a plethora of cellular proteins, it is involved in the regulation of nearly all cellular activities. [less ▲]

Protein-protein interactions and gene expression regulation in HTLV-1 infected cells.

in Frontiers in Bioscience : A Journal and Virtual Library (2009), 14

Human T-cell leukemia virus type 1 (HTLV-1) propagates in CD4 or CD8 T cells and, after extended latency periods of 30-50 years, causes a rapidly fatal leukemia called adult T-cell leukemia/lymphoma (ATL ... [more ▼]

Human T-cell leukemia virus type 1 (HTLV-1) propagates in CD4 or CD8 T cells and, after extended latency periods of 30-50 years, causes a rapidly fatal leukemia called adult T-cell leukemia/lymphoma (ATL). Infection with HTLV-1 is also associated with a degenerative neuromuscular disease referred to as tropical spastic paraparesis or HTLV-1-associated myelopathy. HTLV genome, in addition to the structural proteins and retroviral enzymes, codes for a region at its 3' end originally designated pX. The products of this region (Tax, Rex, p12I, p13II, p30II and HBZ) play important roles in deregulation of cellular functions by either directly disrupting cellular factors or altering transcription of viral and cellular genes. Here, we will review current knowledge of protein-protein interactions that regulate transcriptional functions of proteins encoded by the pX region. [less ▲]

Protein Phosphatase 2a Controls The Activity Of Histone Deacetylase 7 During T Cell Apoptosis And Angiogenesis

in Proceedings of the National Academy of Sciences of the United States of America (2008), 105(12), 4727-4732

The HTLV-1 Tax interactome.

in Retrovirology (2008), 5

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to ... [more ▼]

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far. [less ▲]

Cell dynamics and immune response to BLV infection: a unifying model

in Frontiers in Bioscience : A Journal and Virtual Library (2007), 12

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the ... [more ▼]

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms. [less ▲]

Homologies entre les deux retrovirus BLV et HTLV-1 et developpement d'une nouvelle approche therapeutique basee sur la levee de la latence virale.

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (2007), 11(2),

Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human.

in Retrovirology (2007), 4(1), 18

In 1871, the observation of yellowish nodules in the enlarged spleen of a cow was considered to be the first reported case of bovine leukemia. The etiological agent of this lymphoproliferative disease ... [more ▼]

In 1871, the observation of yellowish nodules in the enlarged spleen of a cow was considered to be the first reported case of bovine leukemia. The etiological agent of this lymphoproliferative disease, bovine leukemia virus (BLV), belongs to the deltaretrovirus genus which also includes the related human T-lymphotropic virus type 1 (HTLV-1). This review summarizes current knowledge of this viral system, which is important as a model for leukemogenesis. Recently, the BLV model has also cast light onto novel prospects for therapies of HTLV induced diseases, for which no satisfactory treatment exists so far. [less ▲]

Les chémokines et leurs récepteurs : rôle dans les infections virales et dans les pathologies cancéreuses

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (2007)

Class IIa histone deacetylases: regulating the regulators.

in Oncogene (2007), 26(37),

n the last decade, the identification of enzymes that regulate acetylation of histones and nonhistone proteins has revealed the key role of dynamic acetylation and deacetylation in various cellular ... [more ▼]

n the last decade, the identification of enzymes that regulate acetylation of histones and nonhistone proteins has revealed the key role of dynamic acetylation and deacetylation in various cellular processes. Mammalian histone deacetylases (HDACs), which catalyse the removal of acetyl groups from lysine residues, are grouped into three classes, on the basis of similarity to yeast counterparts. An abundance of experimental evidence has established class IIa HDACs as crucial transcriptional regulators of various developmental and differentiation processes. In the past 5 years, a tremendous effort has been dedicated to characterizing the regulation of these enzymes. In this review, we summarize the latest discoveries in the field and discuss the molecular and structural determinants of class IIa HDACs regulation. Finally, we emphasize that comprehension of the mechanisms underlying class IIa HDAC functions is essential for potential therapeutic applications. [less ▲]