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
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    • "Tax, a non-structural protein and the main driver of viral transcription, potently activates viral transcription during the early phase of infection by recruiting multiple cellular transcription factors[54]. Three conserved 21-bp repeat elements, known as the Tax-responsive element 1 (TRE-1), bind the cyclic AMP response element binding protein (CREB) at the TRE-1 site through its N-terminus (NTD)55565758596061, while the C-terminal domain (CTD) of Tax is believed to promote the transcriptional initiation and RNA polymerase elongation by directly interacting with the TATA binding protein[5,62]. The Tax-CREB promoter complex recruits the multifunctional cellular coactivators CREB binding protein (CBP), p300, and the p300/CBP-associated factor to the LTR636465666768. "
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    ABSTRACT: Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle-both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies.
    Preview · Article · Jan 2016 · Viruses
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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.
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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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