Functional and biochemical interaction of the HTLV-I Tax1 transactivator with TBP

Laboratoire de Biologie Moléculaire et Cellulaire, Ecole Normale Supérieure de Lyon, UMR 49, CNRS, France.
The EMBO Journal (Impact Factor: 10.43). 12/1993; 12(11):4269-78.
Source: PubMed


The human T-cell leukemia virus type I (HTLV-I) codes for the potent transcriptional activator, Tax1, which induces the enhancer activity of various enhancer elements. In the case of the 21 bp enhancer of the HTLV-I provirus, this induction is correlated with the association of Tax1 with this DNA element via a specific cellular factor. That the indirect association of Tax1 with DNA can lead to transcriptional activation has also been supported by the study of chimeric GAL4-Tax1 proteins. The GAL4-Tax1 stimulatory effect exhibits a strong self-squelching. In order to determine whether Tax1 interacts directly with the general transcription factors or via intermediary molecules, we have analyzed how overexpression of the TATA binding protein (TBP) and TFIIB protein affects the squelching curve of GAL4-Tax1. The data presented here show that overexpression of TBP strongly increases the stimulatory effect of GAL4-Tax1, causes a displacement of the maximum of the squelching curve and partially alleviates the squelching. Under similar conditions TFIIB exhibited little effect. From these results we conclude that Tax1 can increase the recruitment of TBP by directly interacting with this protein. Biochemical experiments with purified proteins produced in bacteria confirmed that Tax1 can interact with TBP but not with TFIIB. Tax1 interacts with the conserved C-terminal part of TBP. Analysis of the ability of different mutants of Tax1 fused to the GAL4 DNA binding domain to activate transcription and to associate with TBP, showed that these activities are correlated. However, since one transcriptionally inactive mutant was able to interact efficiently with TBP in vitro, it would appear that an event other than the Tax1-TBP contact also intervenes in the activation of transcription by Tax1.

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Available from: Raphaël Rousset, Oct 14, 2015
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    • "Another mechanism by which HTLV-1 may influence the host cell miRNA expression profile is through the activation of host transcription factors. Important transcription factors and cellular kinases which interact directly with the viral protein Tax are CREB, serum-responsive factor (SRF), NFκB , Cyclins D2 and D3, mitotic check point regulators (MAD1), cyclin dependent kinases (CDKs), the CDK inhibitors p16 INK4A and p21 (WAF1/CIP1) , and the tumor suppressor p53 (Caron et al., 1993; Suzuki et al., 1994; Yin et al., 1995, 1998; Clemens et al., 1996; Colgin and Nyborg, 1998; Harrod et al., 1998; Gachon et al., 2000; Nicot et al., 2000; Xiao et al., 2001; Kashanchi and Brady, 2005; Easley et al., 2010). In particular, the NF-κB pathways activation is a hall mark of HTLV-1 infection and may be the result of direct interaction between Tax and the NF-κB regulatory subunit IKKγ (Sun and Yamaoka, 2005; Yasunaga and Matsuoka, 2011). "
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    ABSTRACT: The human retroviruses HIV-1 and HTLV-1/HTLV-2 share similar routes of transmission but cause significantly different diseases. In this review we have outlined the immune mediated mechanisms by which HTLVs affect HIV-1 disease in co-infected hosts. During co-infection with HIV-1, HTLV-2 modulates the cellular microenvironment favoring its own viability and inhibiting HIV-1 progression. This is achieved when the HTLV-2 proviral load is higher than that of HIV-1, and thanks to the ability of HTLV-2 to: (i) up-regulate viral suppressive CCL3L1 chemokine expression; (ii) overcome HIV-1 capacity to activate the JAK/STAT pathway; (iii) reduce the activation of T and NK cells; (iv) modulate the host miRNA profiles. These alterations of immune functions have been mainly attributed to the effects of the HTLV-2 regulatory protein Tax and suggest that HTLV-2 exerts a protective role against HIV-1 infection. Contrary to HIV-1/HTLV-2, the effect of HIV-1/HTLV-1 co-infection on immunological and pathological conditions is still controversial. There is evidence that indicates a worsening of HIV-1 infection, while other evidence does not show clinically relevant effects in HIV-positive people. Possible differences on innate immune mechanisms and a particularly impact on NK cells are becoming evident. The differences between the two HIV-1/HTLV-1 and HIV-1/HTLV-2 co-infections are highlighted and further discussed.
    Frontiers in Microbiology 12/2013; 4:372. DOI:10.3389/fmicb.2013.00372 · 3.99 Impact Factor
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    • "The coactivator-associated arginine methyltransferase 1 (CARM1) has been reported to interact and synergize with both CIITA and Tax-1 to optimally activate transcription of their target genes (Zika et al., 2005; Jeong et al., 2006). Aside from their interactions with specific DNA-bound factors and chromatin modifying proteins, Tax and CIITA bind also component of the general transcriptional machinery, such as TFIID, to direct transcription initiation (Caron et al., 1993; Fontes et al., 1999a). There is also evidence that both transcription factors recruit the P-TEFb to the target promoters by interacting with the cyclin T1 subunit (Kanazawa et al., 2000; Zhou et al., 2006; Cho et al., 2007). "
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    ABSTRACT: The activation of CD4(+) T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution.
    Frontiers in Microbiology 08/2013; 4:234. DOI:10.3389/fmicb.2013.00234 · 3.99 Impact Factor
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    • "Instead of binding to DNA directly, Tax induces transcription of TREs, catalyzes post-translational modifications (PTMs) of TRE-binding factors, and forms complexes with transcription factors. Tax interacts with numerous important transcription factors and cellular kinases but of these CRE Binding Protein (CREB) is key to viral transcription (Caron et al., 1993; Suzuki et al., 1994; Yin et al., 1995, 1998; Clemens et al., 1996; Colgin and Nyborg, 1998; Harrod et al., 1998; Gachon et al., 2000; Nicot et al., 2000; Xiao et al., 2001; Kashanchi and Brady, 2005; Easley et al., 2010). The interaction of Tax with CREB occurs in order to bind to cis-acting replication element (CRE) enhancer sequences on the viral promoter, which is a critical step in viral transactivation and in the formation of the pre-initiation complex (Kwok et al., 1996; Giebler et al., 1997; Kashanchi et al., 1998; Wu et al., 2004; Easley et al., 2010). "
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    ABSTRACT: Human T-lymphotropic virus 1 (HTLV-1) was the first human retrovirus to be discovered and is the causative agent of adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The importance of microRNA (miRNA) in the replicative cycle of several other viruses, as well as in the progression of associated pathologies, has been well established in the past decade. Moreover, involvement of miRNA alteration in the HTLV-1 life cycle, and in the progression of its related oncogenic and neurodegenerative diseases, has recently come to light. Several HTLV-1 derived proteins alter transcription factor functionalities, interact with chromatin remodelers, or manipulate components of the RNA interference (RNAi) machinery, thereby establishing various routes by which miRNA expression can be up- or down-regulated in the host cell. Furthermore, the mechanism of action through which dysregulation of host miRNAs affects HTLV-1 infected cells can vary substantially and include mRNA silencing via the RNA-induced silencing complex (RISC), transcriptional gene silencing, inhibition of RNAi components, and chromatin remodeling. These miRNA-induced changes can lead to increased cell survival, invasiveness, proliferation, and differentiation, as well as allow for viral latency. While many recent studies have successfully implicated miRNAs in the life cycle and pathogenesis of HTLV-1 infections, there are still significant outstanding questions to be addressed. Here we will review recent discoveries elucidating HTLV-1 mediated manipulation of host cell miRNA profiles and examine the impact on pathogenesis, as well as explore future lines of inquiry that could increase understanding in this field of study.
    Frontiers in Genetics 12/2012; 3:295. DOI:10.3389/fgene.2012.00295
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