Highlights on distinctive structural and functional properties of HTLV Tax proteins

Romanelli, Maria Grazia; Diani, Erica; Bergamo, Elisa; Casoli, C; Ciminale, Vincenzo; Bex, Françoise; Bertazzoni, Umberto

doi:10.3389/fmicb.2013.00271

Cited by 46 publications

(44 citation statements)

References 168 publications

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“…28,29 Here, we demonstrate in several cell lines that HTLV-1-transformed cells remain strictly dependent on continued Tax expression for their survival in culture. Extinction of HTLV-1 HBZ in SLB-1 T cells modestly reduces their proliferation, 30 whereas Tax silencing induces cell death (Figure 1).…”

Section: Discussionmentioning

confidence: 75%

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

Dassouki

Şahin

Hajj

et al. 2015

Blood

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Key Points• Survival of ATL cells depends on continuous Tax expression.• Arsenic/interferon combination induces SUMO/PML/RNF4-mediated Tax degradation.The human T-cell lymphotropic virus type I (HTLV-1) Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapyresistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or human patients. However, the role of Tax loss in ATL response is disputed, and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1-transformed cells are dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/ interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hypersumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins. (Blood. 2015;125(3):474-482)

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Section: Discussionmentioning

confidence: 75%

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

Dassouki

Şahin

Hajj

et al. 2015

Blood

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“…Similar to other retroviruses the genome contains two long terminal repeat (LTR) sequences that drive expression of the viral structural proteins. The viruses also express further regulatory proteins including Tax-1, Rex, p30, and HTLV-1 basic leucine zipper factor (HBZ) [111]. The most intensively studied protein is Tax-1, as it is required for the transforming ability of HTLV-1 [112].…”

Section: The Role Of Nf-κb In Htlv-1 Infectionmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

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“…HTLV-1, another human retrovirus and the cause of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), has also been shown to incorporate viral proteins into shed exosomes. Jaworski et al [98] found that HTLV-1-infected cell lines shed exosomes containing Tax, a pleiotropic transactivating protein implicated in the immune dysregulation associated with infection [99,100]. Tax appears to be targeted for exosome entry by ubiquitination [98,101], which was noted earlier to be an important target for ESCRT machinery.…”

Section: Htlvmentioning

confidence: 96%

Exosomes in Viral Disease

2016

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Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever.

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Highlights on distinctive structural and functional properties of HTLV Tax proteins

Cited by 46 publications

References 168 publications

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

The intricate interplay between RNA viruses and NF-κB

Exosomes in Viral Disease

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