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1.
Retrovirology ; 9: 77, 2012 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-23009398

RESUMO

BACKGROUND: The Tax protein encoded by Human T-lymphotropic virus type 1 (HTLV-1) is a powerful activator of the NF-κB pathway, a property critical for HTLV-1-induced immortalization of CD4⁺ T lymphocytes. Tax permanently stimulates this pathway at a cytoplasmic level by activating the IκB kinase (IKK) complex and at a nuclear level by enhancing the binding of the NF-κB factor RelA to its cognate promoters and by forming nuclear bodies, believed to represent transcriptionally active structures. In previous studies, we reported that Tax ubiquitination and SUMOylation play a critical role in Tax localization and NF-κB activation. Indeed, analysis of lysine Tax mutants fused or not to ubiquitin or SUMO led us to propose a two-step model in which Tax ubiquitination first intervenes to activate IKK while Tax SUMOylation is subsequently required for promoter activation within Tax nuclear bodies. However, recent studies showing that ubiquitin or SUMO can modulate Tax activities in either the nucleus or the cytoplasm and that SUMOylated Tax can serve as substrate for ubiquitination suggested that Tax ubiquitination and SUMOylation may mediate redundant rather than successive functions. RESULTS: In this study, we analyzed the properties of a new Tax mutant that is properly ubiquitinated, but defective for both nuclear body formation and SUMOylation. We report that reducing Tax SUMOylation and nuclear body formation do not alter the ability of Tax to activate IKK, induce RelA nuclear translocation, and trigger gene expression from a NF-κB promoter. Importantly, potent NF-κB promoter activation by Tax despite low SUMOylation and nuclear body formation is also observed in T cells, including CD4⁺ primary T lymphocytes. Moreover, we show that Tax nuclear bodies are hardly observed in HTLV-1-infected T cells. Finally, we provide direct evidence that the degree of NF-κB activation by Tax correlates with the level of Tax ubiquitination, but not SUMOylation. CONCLUSIONS: These data reveal that the formation of Tax nuclear bodies, previously associated to transcriptional activities in Tax-transfected cells, is dispensable for NF-κB promoter activation, notably in CD4⁺ T cells. They also provide the first evidence that Tax SUMOylation is not a key determinant for Tax-induced NF-κB activation.


Assuntos
Produtos do Gene tax/metabolismo , Espaço Intranuclear/metabolismo , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Ativação Transcricional , Substituição de Aminoácidos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Produtos do Gene tax/genética , Genes Reporter , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Quinase I-kappa B/metabolismo , Luciferases de Renilla/biossíntese , Luciferases de Renilla/genética , Microscopia Confocal , NF-kappa B/fisiologia , Ligação Proteica , Transporte Proteico , Proteínas Recombinantes de Fusão/metabolismo , Proteína SUMO-1/metabolismo , Transdução de Sinais , Sumoilação , Transcrição Gênica , Ubiquitinação
2.
Retrovirology ; 6: 28, 2009 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-19284574

RESUMO

BACKGROUND: HIV-1 uses cellular co-factors for virion formation and release. The virus is able to incorporate into the viral particles host cellular proteins, such as tetraspanins which could serve to facilitate HIV-1 egress. Here, we investigated the implication of several tetraspanins on HIV-1 formation and release in chronically infected T-lymphoblastic cells, a model that permits the study of the late steps of HIV-1 replication. RESULTS: Our data revealed that HIV-1 Gag and Env structural proteins co-localized with tetraspanins in the form of clusters. Co-immunoprecipitation experiments showed that Gag proteins interact, directly or indirectly, with CD81, and less with CD82, in tetraspanin-enriched microdomains composed of CD81/CD82/CD63. In addition, when HIV-1 producing cells were treated with anti-CD81 antibodies, or upon CD81 silencing by RNA interference, HIV-1 release was significantly impaired, and its infectivity was modulated. Finally, CD81 downregulation resulted in Gag redistribution at the cell surface. CONCLUSION: Our findings not only extend the notion that HIV-1 assembly can occur on tetraspanin-enriched microdomains in T cells, but also highlight a critical role for the tetraspanin CD81 on the late steps of HIV replication.


Assuntos
Antígenos CD/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Linfócitos T/virologia , Replicação Viral/fisiologia , Linhagem Celular , Regulação para Baixo , HIV-1/patogenicidade , Imunoprecipitação , Proteínas de Membrana/metabolismo , Interferência de RNA , Tetraspanina 28 , Proteínas Virais/metabolismo , Vírion/isolamento & purificação , Vírion/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
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