Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

Bertazzoni, Umberto; Turci, Marco; Avesani, Francesca; Gennaro, Gianfranco Di; Bidoia, Carlo; Romanelli, Maria Grazia

doi:10.3390/v3050541

Cited by 37 publications

(46 citation statements)

References 113 publications

(149 reference statements)

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“…In the noncanonical pathway, Tax-1-IKK␥ interaction facilitates assembly of the Tax-1/IKK␣ complex, bypassing the requirement of NIK for IKK kinase activation (34)(35)(36)(37). Unlike Tax-1, Tax-2 is able to activate only the canonical NF-B route (38,39). Besides binding to IKK␥ in the cytoplasm, Tax-1 promotes NF-B activation in the nucleus by interacting with RelA and stabilizing the binding of p50/RelA to NF-B-responsive promoters (24,40).…”

mentioning

confidence: 99%

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

Forlani

Abdallah

Accolla

et al. 2016

J Virol

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Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, a key protein in HTLV-1-induced T cell transformation, deregulates diverse cell signaling pathways. Among them, the NF-B pathway is constitutively activated by Tax-1, which binds to NF-B proteins and activates the IB kinase (IKK). Upon phosphorylation-dependent IB degradation, NF-B migrates into the nucleus, mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA (class II transactivator), endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-B pathway by Tax-1 and map the region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with impaired migration of RelA into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-B activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKK␥ and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-B-responsive genes. Thus, CIITA inhibits cytoplasmic and nuclear steps of Tax-1-mediated NF-B activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential.

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mentioning

confidence: 99%

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

Forlani

Abdallah

Accolla

et al. 2016

J Virol

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“…The differential functional characteristics of Tax1 and Tax2 most likely explain the differences in disease conditions associated with HTLV-1 and HTLV-2. 8 In clinical scenarios where overexpression of Tax1 and Tax2 occurs, increased transactivation of cellular genes might result in immune dysregulation in affected individuals. This has been clearly shown to be the case in HTLV-1-infected individuals with HTLV-1-associated myelopathy, in whom very high levels of HTLV-1 tax/rex mRNA can be detected.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Several recent studies suggest three conclusions regarding HIV/HTLV coinfections: (1) HIV-1 and HTLV-1 coinfections are often seen in the context of patients with high CD4 + T cell counts and who manifest neurological complications 5,6 ; (2) HIV-1 and HTLV-2 coinfections have been linked in some cases to a ''long-term nonprogressor'' phenotype 3,7 ; and (3) differential function and/or overexpression of the HTLV-1 and HTLV-2 Tax proteins are likely to play a pivotal role in the clinical and immunological manifestations of HIV/HTLV coinfections. 8 Two retrospective case-controlled cohort studies investigating the clinical outcomes and survival probabilities among persons coinfected with HIV-1 and HTLV-1 or -2 showed that HTLV-2 coinfections resulted in improved survival and delayed progression to AIDS. 3,7 These findings have been attributed in part to the ability of HTLV-2 to activate production of antiviral chemokines and to downregulate the CCR5 coreceptor on lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV Type 1 Replication by Human T Lymphotropic Virus Types 1 and 2 Tax Proteinsin Vitro

Barrios

Castillo²,

Giam³

et al. 2013

AIDS Research and Human Retroviruses

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Patients with HIV-1 and human T-lymphotropic virus type 2 (HTLV-2) coinfections often exhibit a clinical course similar to that seen in HIV-1-infected individuals who are long-term nonprogressors. These findings have been attributed in part to the ability of HTLV-2 to activate production of antiviral chemokines and to downregulate the CCR5 coreceptor on lymphocytes. To further investigate these observations, we tested the ability of recombinant Tax1 and Tax2 proteins to suppress HIV-1 viral replication in vitro. R5-tropic HIV-1 (NLAD8)-infected peripheral blood mononuclear cells (PBMCs) were treated daily with recombinant Tax1 and Tax2 proteins (dosage range 1-100 pM). Culture supernatants were collected at intervals from days 1 to 22 postinfection and assayed for levels of HIV-1 p24 antigen by ELISA. Treatment of PBMCs with Tax2 protein resulted in a significant reduction in HIV-1 p24 antigen levels ( p < 0.05) at days 10, 14, and 18 postinfection compared to HIV-1-infected or mock-treated PBMCs. This was preceded by the detection of increased levels of CCchemokines MIP-1a/CCL3, MIP-1b/CCL4, and RANTES/CCL5 on days 1-7 of infection. Similar, but less robust inhibition was observed in Tax1-treated PBMCs. These results support the contention that Tax1 and Tax2 play a role in generating antiviral responses against HIV-1 in vivo and in vitro.

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“…The kinases involved are unknown and could represent a genuine target for Tax-oriented therapy. Only the pleiotropic and constitutively active CK2 (formerly known as casein kinase 2) is proven to phosphorylate Tax in vitro, modulating the functions associated with its C-terminus [70] , which is extremely important for the binding, with subsequent inhibition, of class I PDZ-containing proteins, some of them tumor suppressors with scaffold function [98,99] . Furthermore, advanced and highly sensitive techniques, such as tandem mass spectrometry, struggle to detect Ser-300/301 phosphorylation or are entirely unable to detect Ser-160 phosphorylation, important for Tax function [69] .…”

Section: Tax Phosphorylationmentioning

confidence: 99%

“…A recent review described the known HTVL-1/2B Tax differences in NF-κB activation and localization, and showed how PTMs affect the two homologue proteins that share 85 % of sequence similarity [99] . HTLV-2B Tax is SUMOylated at lower levels than HTLV-1 Tax and ubiquitinated [100] .…”

Section: Tax-2b Ptmsmentioning

confidence: 99%

Human T-lymphotropic virus proteins and post-translational modification pathways

Bidoia

2012

WJV

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Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications (PTMs). PTMs alter the conformation, the stability, the localization, and hence the pattern of interactions of the targeted protein. Cell pathways involve the activation of enzymes, like kinases, ligases and transferases, that, once activated, act on many proteins simultaneously, altering the state of the cell and triggering the processes they are involved in. Viruses enter a balanced system and hijack the cell, exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways, with the ultimate consequence to perpetuate through their replication. Human T-lymphotropic virus type 1 (HTLV-1) is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions. HTLV-1 protein activity is controlled by PTMs and, in turn, viral activity is associated with the modulation of cellular pathways based on PTMs. More knowledge is acquired about the PTMs involved in the activation of its proteins, like Tax, Rex, p12, p13, p30, HTLV-I basic leucine zipper factor and Gag. However, more has to be understood at the biochemical level in order to counteract the associated fatal outcomes. This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins.

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Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

Cited by 37 publications

References 113 publications

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

Inhibition of HIV Type 1 Replication by Human T Lymphotropic Virus Types 1 and 2 Tax Proteinsin Vitro

Human T-lymphotropic virus proteins and post-translational modification pathways

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