Human T-Cell Lymphotropic Virus Type 1 Tax Represses c-Myb-Dependent Transcription through Activation of the NF-κB Pathway and Modulation of Coactivator Usage

Nicot, Christophe; Mahieux, Renaud; Pise-Masison, Cynthia A.; Brady, John; Gessain, Antoine; Shoji, Yasuhiro; Franchini, Genoveffa

doi:10.1128/mcb.21.21.7391-7402.2001

Cited by 33 publications

(36 citation statements)

References 71 publications

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“…Western blots were carried out with equal amounts of protein extracts to confirm the expression of transfected constructs. As a negative control, we used pGL3-MRE (myb-responsive element) luciferase plasmid (27) and repeated the same experiment with a dose-dependent increase of p30. PU.1 was detected with T-21 antibody, c-Myb with C-19, p30 with 3F10, actin with C-11 (Santa Cruz Biotechnology), and ␤-tubulin with H-235 (Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

The HTLV-I p30 Interferes with TLR4 Signaling and Modulates the Release of Pro- and Anti-inflammatory Cytokines from Human Macrophages

Datta

Sinha-Datta

Dhillon

et al. 2006

Journal of Biological Chemistry

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Whereas adaptive immunity has been extensively studied, very little is known about the innate immunity of the host to HTLV-I infection. HTLV-I-infected ATL patients have pronounced immunodeficiency associated with frequent opportunistic infections, and in these patients, concurrent infections with bacteria and/or parasites are known to increase risks of progression to ATL. The Toll-like receptor-4 (TLR4) activation in response to bacterial infection is essential for dendritic cell maturation and links the innate and adaptive immune responses. Recent reports indicate that TLR4 is targeted by viruses such as RSV, HCV, and MMTV. Here we report that HTLV-I has also evolved a protein that interferes with TLR4 signaling; p30 interacts with and inhibits the DNA binding and transcription activity of PU.1 resulting in the down-regulation of the TLR4 expression from the cell surface. Expression of p30 hampers the release of pro-inflammatory cytokines MCP-1, TNF-␣, and IL-8 and stimulates release of anti-inflammatory IL-10 following stimulation of TLR4 in human macrophage. Finally, we found that p30 increases phosphorylation and inactivation of GSK3-␤ a key step for IL-10 production. Our study suggests a novel function of p30, which may instigate immune tolerance by reducing activation of adaptive immunity in ATL patients.

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Section: Methodsmentioning

confidence: 99%

The HTLV-I p30 Interferes with TLR4 Signaling and Modulates the Release of Pro- and Anti-inflammatory Cytokines from Human Macrophages

Datta

Sinha-Datta

Dhillon

et al. 2006

Journal of Biological Chemistry

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“…In this regard, NF-kB is responsible for Tax-mediated inhibition of certain genes involved in DNA repair and cell cycle checkpoint regulation, especially those encoding b-polymerase and p53 (Uittenbogaard et al, 1994(Uittenbogaard et al, , 1995. This function of NF-kB is indirectly mediated through repressing the transactivation activity of bHLH factors, such as c-Myb (Nicot et al, 2001). NF-kB inhibits the function of c-Myb through RelA-mediated sequestration of the coactivator proteins CBP/p300.…”

Section: Implications Of Nf-jb In Htlv-i-induced T-cell Transformationmentioning

confidence: 99%

Activation of NF-κB by HTLV-I and implications for cell transformation

2005

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“…Activity was calculated as the ratio of the values of firefly luciferase to Renilla luciferase activities, and results expressed as -fold activation are representative of two independent sets of experiments. In vitro transcription/translation reactions were performed with pMH-p30-HA using rabbit reticulocyte lysates as reported previously (15). Immunoprecipitation was performed with antibody 12CA5 (Roche Diagnostics).…”

Section: Plasmid Construction and Site-directed Mutagenesis-p30mentioning

confidence: 99%

Human T-cell Leukemia Virus Type I p30 Nuclear/Nucleolar Retention Is Mediated through Interactions with RNA and a Constituent of the 60 S Ribosomal Subunit

Ghorbel

Sinha-Datta

Dundr

et al. 2006

Journal of Biological Chemistry

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Nucleoli are the main site of ribosome biogenesis, a highly complex process leading to the production of pre-ribosomal particles, which are then released into the nucleoplasm and exported to the cytoplasm as mature ribosomal subunits (1). In contrast to other cellular compartments, the nucleolus is not membrane-limited; its structure is maintained by a major accumulation of ribosomal rRNA and proteins such as nucleolin and protein B23. Most proteins are only transiently retained in the nucleolus through protein or RNA interactions, and proteins with long resident times usually harbor specific signals (2). Rather than being nucleolar localization signals (NoLS), 2 these signals tend to be nucleolar retention signals (NoRS). With very few exceptions (3), these NoRS are generally characterized by arginine-and lysine-rich sequences of highly variable sizes, ranging from five amino acids for angiogenin up to several tens for nucleolin (4, 5). Often, amino acid sequence analysis fails to predict putative NoRS, especially when they overlap nuclear localization signals (NLS). The nucleolus, the site of transient sequestration and maturation of several cellular factors, is critically involved in the control of the cell cycle, DNA repair, aging, and mRNA export. Many viruses encode nucleolar proteins, which are involved in replication of viral genomes (6) as well as in transcriptional and post-transcriptional regulation of gene expression (7).We found recently that the viral p30 protein is a novel posttranscriptional repressor of human T-cell leukemia virus type I (HTLV-I) replication (8). p30 is a serine/arginine-rich nuclear/ nucleolar protein that complexes with and retains the viral tax/ rex mRNA in the nuclei of infected cells. Hence, decreased expression of the positive regulators Tax and Rex results in inhibition of virus replication (8). In this study, we investigated the mechanisms underlying p30 retention. Our results show that p30 utilizes multiple strategies and harbors two nucleolar retention domains. Consistent with its role in RNA trafficking, p30 nuclear/nucleolar retention is partially dependent on de novo mRNA transcription. We also report that p30 interacts with a nucleolar constituent of the large ribosomal subunit L18a, a protein shown previously (12,(32)(33)(34) to modulate internal initiation of translation.

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Human T-Cell Lymphotropic Virus Type 1 Tax Represses c-Myb-Dependent Transcription through Activation of the NF-κB Pathway and Modulation of Coactivator Usage

Abstract: The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation.

Cited by 33 publications

References 71 publications

The HTLV-I p30 Interferes with TLR4 Signaling and Modulates the Release of Pro- and Anti-inflammatory Cytokines from Human Macrophages

The HTLV-I p30 Interferes with TLR4 Signaling and Modulates the Release of Pro- and Anti-inflammatory Cytokines from Human Macrophages

Activation of NF-κB by HTLV-I and implications for cell transformation

Human T-cell Leukemia Virus Type I p30 Nuclear/Nucleolar Retention Is Mediated through Interactions with RNA and a Constituent of the 60 S Ribosomal Subunit

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