Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5–10 million people worldwide and is the infectious cause of adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), dermatitis, and uveitis. Unlike other oncogenic retroviruses, HTLV-1 does not capture a cellular proto-oncogene or induce proviral insertional mutagenesis. HTLV-1 is a trans-activating retrovirus and encodes accessory proteins that induce cellular transformation over an extended period of time, upwards of several years to decades. Inarguably the most important viral accessory protein involved in transformation is Tax. Tax is a multifunctional protein that regulates several different pathways and cellular processes. This single viral protein is able to modulate viral gene expression, activate NF-κB signaling pathways, deregulate the cell cycle, disrupt apoptosis, and induce genomic instability. The summation of these processes results in cellular transformation and virus-mediated oncogenesis. Interestingly, HTLV-1 also encodes a protein called Hbz from the antisense strand of the proviral genome that counters many Tax functions in the infected cell, such as Tax-mediated viral transcription and NF-κB activation. However, Hbz also promotes cellular proliferation, inhibits apoptosis, and disrupts genomic integrity. In addition to viral proteins, there are other cellular factors such as MEF-2, superoxide-generating NAPDH oxidase 5-α (Nox5α), and PDLIM2 which have been shown to be critical for HTLV-1-mediated T-cell transformation. This review will highlight the important viral and cellular factors involved in HTLV-1 transformation and the available in vitro and in vivo tools used to study this complex process.

• HTLV-1
• Hbz
• Tax
• oncogenesis
• transformation

• HTLV-1
• NF-κB
• T-cell leukemia
• autophagy
• tax

• ATLL
• HTLV-1
• NF-κB
• Tax
• apoptosis

• R01 CA135362 NCI NIH HHS
• RO1CA135362 NIH HHS

• Cancer therapy
• Preclinical research

• Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)

• HBZ
• HTLV-1
• NF-κB
• Tax
• miRNA

• ATLL
• Genomic instability
• HTLV-1
• Microtubule
• NF-kappa B
• Stathmin
• Tax
• Tubulin
• Viral oncoprotein
• p30

• ATLL
• Angiogenesis
• HBZ
• HTLV-1
• Lymphoma
• ROS
• TIGAR
• Tax
• Xenograft
• p30(II)

• Animals
• Apoptosis Regulatory Proteins
• Basic-Leucine Zipper Transcription Factors/genetics
• Basic-Leucine Zipper Transcription Factors/metabolism
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/virology
• Carcinogenesis
• Gene Expression Regulation, Viral
• Gene Products, tax/metabolism
• Genes, pX
• Heterografts
• Human T-lymphotropic virus 1/genetics
• Human T-lymphotropic virus 1/metabolism
• Human T-lymphotropic virus 1/physiology
• Humans
• Intracellular Signaling Peptides and Proteins/genetics
• Lymphoma/virology
• Mice
• Mitophagy
• Neovascularization, Pathologic
• Oxidative Stress
• Phosphoric Monoester Hydrolases
• Reactive Oxygen Species/metabolism
• Retroviridae Proteins/genetics
• Retroviridae Proteins/metabolism

• P01 CA100730 NCI NIH HHS
• R15 CA158945 NCI NIH HHS
• R15 CA202265 NCI NIH HHS

• HTLV-1
• NF-κB
• Senescence
• leukemia
• tax

Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.

• NF-kB
• NF-kappaB
• cancer
• immune response
• inflammation
• signaling
• therapy
• treatment

• Electrophoresis, Polyacrylamide Gel
• Enzyme Activation/physiology
• Gene Products, tax/metabolism
• HEK293 Cells
• HTLV-I Infections/metabolism
• Human T-lymphotropic virus 1/pathogenicity
• Humans
• I-kappa B Kinase/metabolism
• Immunoblotting
• Immunoprecipitation
• Jurkat Cells
• NF-kappa B/metabolism
• Real-Time Polymerase Chain Reaction
• Signal Transduction/physiology
• Transfection

• MEXT/JSPS KAKENHI

HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

• DNA damage response
• HTLV-1
• K63-linked polyubiquitin
• RNF8
• UBC13
• adult T-cell leukemia
• genomic instability
• latency and persistence
• senescence

• Basic-Leucine Zipper Transcription Factors/metabolism
• Carcinogenesis
• Gene Products, tax/metabolism
• Host-Pathogen Interactions
• Human T-lymphotropic virus 1/pathogenicity
• Humans
• Leukemia-Lymphoma, Adult T-Cell/pathology
• Leukemia-Lymphoma, Adult T-Cell/virology
• Retroviridae Proteins/metabolism
• Virus Latency
• Virus Replication

• R01 CA076595 NCI NIH HHS

The HTLV-1 oncoprotein Tax plays a key role in CD4⁺ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a distinct neurological disorder with inflammatory symptoms and incomplete paralysis of the limbs, and adult T-cell leukemia/lymphoma (ATL), a highly aggressive malignant proliferation of CD4⁺ T lymphocytes. Both TSP/HAM and ATL are mainly driven by the activation of IκB kinase (IKK)-NF-κB stimulated by HTLV-1 oncoprotein Tax. The molecular mechanism by which Tax activates IKK remains unclear. Here, we found that Tax is an E3 ubiquitin ligase, which, together with its cognate ubiquitin-conjugating enzymes (E2s) UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of unanchored free mixed-linkage polyubiquitin chains. The polyubiquitin chains can activate IKK complex directly by binding to the NEMO subunit. Our studies uncovered the essential cellular factors hijacked by HTLV-1 for infection and pathogenesis, as well as the biochemical function and the underlying mechanism of Tax in the process of IKK activation. Our work might shed light on potential development of therapeutics for TSP/HAM and ATL.

• Chromatography, High Pressure Liquid
• Enzyme Activation/physiology
• Gene Knockout Techniques
• Gene Products, tax/metabolism
• HEK293 Cells
• HTLV-I Infections/metabolism
• Humans
• I-kappa B Kinase/metabolism
• Immunoblotting
• Jurkat Cells
• NF-kappa B/metabolism
• Polyubiquitin/biosynthesis
• Signal Transduction/physiology
• Tandem Mass Spectrometry
• Transfection
• Ubiquitin-Protein Ligases/metabolism

• NF-κB
• cell signaling
• death domain
• protein kinase
• ubiquitylation (ubiquitination)

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.

• antiretroviral
• deltaretrovirus
• lentivirus

Human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, impacts a multitude of cellular processes, including I-κB kinase (IKK)/NF-κB signaling, DNA damage repair, and mitosis. These activities of Tax have been implicated in the development of adult T-cell leukemia (ATL) in HTLV-1-infected individuals, but the underlying mechanisms remain obscure. IKK and its upstream kinase, TGFβ-activated kinase 1 (TAK1), contain ubiquitin-binding subunits, NEMO and TAB2/3 respectively, which interact with K63-linked polyubiquitin (K63-pUb) chains. Recruitment to K63-pUb allows cross auto-phosphorylation and activation of TAK1 to occur, followed by TAK1-catalyzed IKK phosphorylation and activation. Using cytosolic extracts of HeLa and Jurkat T cells supplemented with purified proteins we have identified ubiquitin E3 ligase, ring finger protein 8 (RNF8), and E2 conjugating enzymes, Ubc13:Uev1A and Ubc13:Uev2, to be the cellular factors utilized by Tax for TAK1 and IKK activation. In vitro, the combination of Tax and RNF8 greatly stimulated TAK1, IKK, IκBα and JNK phosphorylation. In vivo, RNF8 over-expression augmented while RNF8 ablation drastically reduced canonical NF-κB activation by Tax. Activation of the non-canonical NF-κB pathway by Tax, however, is unaffected by the loss of RNF8. Using purified components, we further demonstrated biochemically that Tax greatly stimulated RNF8 and Ubc13:Uev1A/Uev2 to assemble long K63-pUb chains. Finally, co-transfection of Tax with increasing amounts of RNF8 greatly induced K63-pUb assembly in a dose-dependent manner. Thus, Tax targets RNF8 and Ubc13:Uev1A/Uev2 to promote the assembly of K63-pUb chains, which signal the activation of TAK1 and multiple downstream kinases including IKK and JNK. Because of the roles RNF8 and K63-pUb chains play in DNA damage repair and cytokinesis, this mechanism may also explain the genomic instability of HTLV-1-transformed T cells and ATL cells.

Activation of the NF-κB family of transcription factors by the HTLV-1 oncoprotein, Tax, is causally linked to adult T cell leukemia (ATL) development in HTLV-1-infected individuals, but the underlying mechanisms are not fully understood. NF-κB activation requires the phosphorylation of its inhibitor, IκBα, by IκB kinase (IKK), which marks IκBα for degradation. In this study, we demonstrate that Tax inappropriately activates a ubiquitin E3 ligase, RNF8, and ubiquitin E2 conjugating enzymes, Ubc13:Uev1A/Uev2, to assemble long lysine 63-linked polyubiquitin (K63-pUb) chains, which function as signaling platforms for polyubiquitin-binding TGFβ-activated kinase 1 (TAK1) and IKK to congregate and become activated. Because TAK1 mediates the activation of multiple downstream signaling pathways, the mechanism described here can explain the complex effect of Tax on cell signaling. The major functions of RNF8 are to signal cellular DNA damage repair (DDR) and cell division by assembling K63-pUb chains at the site of DNA damage and cell cleavage. As such, the inappropriate activation of RNF8 and the over-abundance of K63-pUb chains in Tax-expressing cells may explain how Tax causes DNA damage and cell division defect.

• Cell Line
• Cell Transformation, Neoplastic/metabolism
• DNA-Binding Proteins/metabolism
• Fluorescent Antibody Technique
• Gene Knockdown Techniques
• Gene Products, tax/metabolism
• Humans
• I-kappa B Kinase/metabolism
• Immunoblotting
• MAP Kinase Kinase Kinases/metabolism
• Polymerase Chain Reaction
• Signal Transduction/physiology
• Transfection
• Ubiquitin-Protein Ligases/metabolism

• R01 CA076595 NCI NIH HHS
• R01 CA140963 NCI NIH HHS
• U01 GM109887 NIGMS NIH HHS
• R01CA140963 NCI NIH HHS

Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-κB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-κB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKγ to the IKK catalytic subunits, IKK-α and -β, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and β. Collectively, these results suggest that FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51.

• Acetylation
• Apoptosis
• HTLV-1
• Transformation
• c-MYC
• p30

• Cell signaling
• HTLV
• IFN
• IKKε
• IRF3
• TBK1
• Tax

Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis.

• Cell Transformation, Neoplastic/metabolism
• Gene Expression Regulation/physiology
• Gene Products, tax/metabolism
• Human T-lymphotropic virus 1/metabolism
• Humans
• Interleukin-17/metabolism
• NF-kappa B/metabolism
• Receptors, Interleukin-17/metabolism
• Signal Transduction/physiology
• T-Lymphocytes/cytology

• P30 CA006973 NCI NIH HHS
• R01 CA135362 NCI NIH HHS
• R01CA135362 NCI NIH HHS

• AMP-Activated Protein Kinases/metabolism
• Animals
• Autophagy/drug effects
• Autophagy/physiology
• Fatty Acids/metabolism
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Fatty Liver/prevention & control
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Liver Neoplasms, Experimental/genetics
• Liver Neoplasms, Experimental/metabolism
• Liver Neoplasms, Experimental/prevention & control
• MAP Kinase Kinase Kinases/deficiency
• MAP Kinase Kinase Kinases/genetics
• MAP Kinase Kinase Kinases/metabolism
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Multiprotein Complexes/antagonists & inhibitors
• Multiprotein Complexes/metabolism
• Oxidation-Reduction
• PPAR alpha/metabolism
• Sirolimus/pharmacology
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism

• R01 CA155120 NCI NIH HHS
• P41 GM103412 NIGMS NIH HHS
• R24 DK080506 NIDDK NIH HHS
• R01AA02172 NIAAA NIH HHS
• P42 ES010337 NIEHS NIH HHS
• R01 DK085252 NIDDK NIH HHS
• R01AA020753 NIAAA NIH HHS
• P50 AA011999 NIAAA NIH HHS
• R01DK085252 NIDDK NIH HHS
• DK080506 NIDDK NIH HHS
• R01CA155120 NCI NIH HHS
• R01 AA020753 NIAAA NIH HHS

Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-κB (nuclear factor kappa-B) pathway, and interactions with host factors.

• HTLV
• NF-κB
• Tax proteins
• signal transduction

Although human T cell leukemia virus type 1 and 2 (HTLV-1 and HTLV-2) share similar genetic organization, they have major differences in their pathogenesis and disease manifestation. HTLV-1 is capable of transforming T lymphocytes in infected patients resulting in adult T cell leukemia/lymphoma whereas HTLV-2 is not clearly associated with lymphoproliferative diseases. Numerous studies have provided accumulating evidence on the involvement of the viral transactivators Tax-1 versus Tax-2 in T cell transformation. Tax-1 is a potent transcriptional activator of both viral and cellular genes. Tax-1 post-translational modifications and specifically ubiquitylation and SUMOylation have been implicated in nuclear factor-kappaB (NF-κB) activation and may contribute to its transformation capacity. Although Tax-2 has similar protein structure compared to Tax-1, the two proteins display differences both in their protein–protein interaction and activation of signal transduction pathways. Recent studies on Tax-2 have suggested ubiquitylation and SUMOylation independent mechanisms of NF-κB activation. In this present review, structural and functional differences between Tax-1 and Tax-2 will be summarized. Specifically, we will address their subcellular localization, nuclear trafficking and their effect on cellular regulatory proteins. A special attention will be given to Tax-1/Tax-2 post-translational modification such as ubiquitylation, SUMOylation, phosphorylation, acetylation, NF-κB activation, and protein–protein interactions involved in oncogenecity both in vivo and in vitro.

• HTLV-1
• HTLV-2
• NF-κB
• Tax-1
• Tax-2

• HTLV-1
• NF-κB
• Tax
• post-translational modification

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.

• Human T-Lymphotropic virus
• Tax
• Rev
• p12
• p13
• Gag
• Post-translational modification

• Autophagy
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/virology
• Cell Cycle
• Cell Transformation, Neoplastic/genetics
• Gene Expression Regulation, Neoplastic
• Gene Products, tax/genetics
• Gene Products, tax/metabolism
• Human T-lymphotropic virus 1/physiology
• Humans
• I-kappa B Kinase/genetics
• I-kappa B Kinase/metabolism
• Leukemia-Lymphoma, Adult T-Cell/genetics
• Leukemia-Lymphoma, Adult T-Cell/metabolism
• Leukemia-Lymphoma, Adult T-Cell/virology
• Membrane Microdomains/metabolism
• Membrane Microdomains/virology
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Protein Binding
• Signal Transduction/genetics

• R01 AI090113 NIAID NIH HHS

• Animals
• Humans
• Immunity, Innate
• Inflammation/enzymology
• Inflammation/metabolism
• Inflammation/therapy
• MAP Kinase Kinase Kinases/antagonists & inhibitors
• MAP Kinase Kinase Kinases/metabolism
• MAP Kinase Kinase Kinases/physiology
• NF-kappa B/metabolism
• Neoplasms/enzymology
• Neoplasms/metabolism
• Neoplasms/therapy
• Signal Transduction
• Transforming Growth Factor beta/metabolism

• Adaptor Proteins, Signal Transducing
• Cell Line
• HIV Envelope Protein gp41/metabolism
• HIV-1/pathogenicity
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Lymphocyte Activation
• NF-kappa B/metabolism
• Protein Binding
• Protein Interaction Mapping
• Simian Immunodeficiency Virus/pathogenicity
• Virus Replication

• R01 AI025328-20 NIAID NIH HHS
• P51 RR000168-50 NCRR NIH HHS
• RR00168 NCRR NIH HHS
• R01 AI025328 NIAID NIH HHS
• R01 AI025328-22 NIAID NIH HHS
• R01 AI025328-23 NIAID NIH HHS
• R01 AI025328-21 NIAID NIH HHS
• 5R01AI025328 NIAID NIH HHS
• P51 RR000168 NCRR NIH HHS
• K26 RR000168 NCRR NIH HHS

Oncoprotein Tax, encoded by the human T-cell leukemia virus type 1 (HTLV1), persistently induces NF-κB activation, which contributes to HTLV1-mediated T-cell transformation. Recent studies suggest that the signaling function of Tax requires its ubiquitination, although how the Tax ubiquitination is regulated remains unclear.

We show here that the deubiquitinase CYLD physically interacts with Tax and negatively regulates the ubiquitination of this viral protein. This function of CYLD is associated with inhibition of Tax-mediated activation of IKK although not that of Tak1. Interestingly, CYLD undergoes constitutive phosphorylation in HTLV1-transformed T cells, a mechanism known to inactivate the catalytic activity of CYLD. Consistently, a phospho-mimetic CYLD mutant fails to inhibit Tax ubiquitination.

These findings suggest that CYLD negatively regulates the signaling function of Tax through inhibition of Tax ubiquitination. Conversely, induction of CYLD phosphorylation may serve as a mechanism by which HTLV1 overrides the inhibitory function of CYLD, leading to the persistent activation of NF-κB.

• Animals
• Cell Communication
• Cytokines/metabolism
• Humans
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation Mediators/metabolism
• Signal Transduction

Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity.

• HTLV
• NF-κB
• PDZ binding motif
• Tax-1
• Tax-2
• cellular localization
• post-translational modifications
• signal transduction

• Gene Products, tax/genetics
• Gene Products, tax/metabolism
• HTLV-I Infections/genetics
• HTLV-I Infections/metabolism
• HTLV-I Infections/virology
• HTLV-II Infections/genetics
• HTLV-II Infections/metabolism
• HTLV-II Infections/virology
• Human T-lymphotropic virus 1/genetics
• Human T-lymphotropic virus 1/metabolism
• Human T-lymphotropic virus 2/genetics
• Human T-lymphotropic virus 2/metabolism
• Humans
• Protein Transport
• Transcriptional Activation

• Animals
• Herpesvirus 4, Human/physiology
• Herpesvirus 8, Human/physiology
• Human T-lymphotropic virus 1/physiology
• Humans
• NF-kappa B/physiology
• Oncogene Proteins, Viral/physiology
• Signal Transduction

• GM084459 NIGMS NIH HHS
• R01 CA068939 NCI NIH HHS
• AI064639 NIAID NIH HHS
• R29 CA068939 NCI NIH HHS
• CA068939 NCI NIH HHS
• R37 AI064639 NIAID NIH HHS
• R01 AI064639 NIAID NIH HHS
• R01 CA103646 NCI NIH HHS
• AI057555 NIAID NIH HHS
• R01 GM084459 NIGMS NIH HHS
• R01 AI057555 NIAID NIH HHS
• CA103646 NCI NIH HHS

• nf-κb
• ubiquitin
• tak1
• ikk
• trafs

• Apoptosis
• Humans
• I-kappa B Proteins/metabolism
• NF-kappa B/metabolism
• NF-kappa B/physiology
• Signal Transduction
• Tumor Necrosis Factor-alpha/metabolism
• Ubiquitin/metabolism
• Ubiquitin/physiology
• Ubiquitination/physiology

• R01 GM063692 NIGMS NIH HHS
• Howard Hughes Medical Institute
• R01-GM63692 NIGMS NIH HHS

Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.

• HBZ
• HTLV-1
• Tax
• cellular transformation
• leukemogenesis

Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiological agent of adult-T-cell leukemia/lymphoma. The HTLV-1 encoded Tax protein is a potent oncoprotein that deregulates gene expression by constitutively activating nuclear factor-κB (NF-κB). Tax activation of NF-κB is critical for the immortalization and survival of HTLV-1-infected T cells. In this review, we summarize the present knowledge on mechanisms underlying Tax-mediated NF-κB activation, with an emphasis on post-translational modifications of Tax.

• Adult-T-cell leukemia/lymphoma
• Human T-cell leukemia virus type 1
• Nuclear factor-κB
• Human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis
• IKK

• P01 CA128115 NCI NIH HHS
• R01 CA135362 NCI NIH HHS
• R01 GM083143 NIGMS NIH HHS

While the human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), to date, its close relative HTLV-2 is not associated with ATL or other types of malignancies. Accumulating evidence shows that HTLV-1 Tax1 and HTLV-2 Tax2 have many shared activities, but the two proteins have a limited number of significantly distinct activities, and these distinctions appear to play key roles in HTLV-1 specific pathogenesis. In this review, we summarize the functions of Tax1 associated with cell survival, cell proliferation, persistent infection as well as pathogenesis. We emphasize special attention to distinctions between Tax1 and Tax2.