HTLV-1 Tax-induced NFκB activation is independent of Lys-63-linked-type polyubiquitination

Gohda, Jin; Irisawa, Masato; Tanaka, Yuetsu; Sato, Shintaro; Ohtani, Kiyoshi; Fujisawa, Jun–ichi; Inoue, Jun‐ichiro

doi:10.1016/j.bbrc.2007.03.125

Cited by 22 publications

(25 citation statements)

References 25 publications

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“…3C). Consistent with our data, Ghoda et al (25) reported that Tax is not able to induce IKK phosphorylation in TAK1 Ϫ/Ϫ MEFs. Further study will be necessary to settle this issue; however, we currently believe that Tax-dependent IKK activation is regulated by a factor other than TAK1.…”

Section: Discussionsupporting

confidence: 93%

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

Suzuki

Singhirunnusorn

Mori

et al. 2007

Journal of Biological Chemistry

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HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-B and CREB (cAMP-response element-binding protein)/ATF.Transforming growth factor-␤-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-B. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-B.Human T-cell lymphotropic virus type 1 (HTLV-1) 2 is known as the cause of adult T-cell leukemia/lymphoma (ATLL). Infection with this virus results in the activation of several transcriptional factors including NF-B and CREB in host CD4ϩ T cells. In particular, the activation of NF-B correlates with the expression of HTLV-1-derived oncoprotein Tax (1). It has been reported that Tax associates with IKK␥ to activate IB kinase (IKK) complex (2).Transforming growth factor-␤-activated kinase 1 (TAK1) is one of the most characterized MAPK kinase kinase family members and is activated by various cellular stresses, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1 (3-13). It has recently been shown that TAK1 participates in diverse cellular functions, including activation and differentiation of T lymphocytes (14 -17). TAK1 functions as an upstream stimulatory molecule of the JNK, p38, and IKK signaling pathways. We have reported that phosphorylation at Thr-187 is essential for TAK1 activation, and TAK1-binding protein 1 (TAB1) and TAB2 are important for inducing phosphorylation (18). Cheung et al. (12) report that the association of TAB1 with p38␣ negatively regulates TAK1 kinase activity by phosphorylating TAB1 at Ser-423, Thr-431, and Ser-438. On the other hand, TAB2 functions as an adaptor protein to recruit TAK1 to TRAF2 (TNF-␣ receptor-associated factor) and TRAF6 in the TNF-␣ and interleukin-1 signaling pathways, respectively (8,11,13). Recently, TAB3 has been reported as a new TAK1-binding protein (13). This molecule has a structure similar to TAB2 and functions as a supportive protein of TAB2.Various alternations of intracellular functions by infecting HTLV-1 and Tax expression result in the onset of ATLL; however, the molecular mechanisms of these alternations are still unclear. The present study investigated whether TAK1 is involved in Tax-dependent NF-B activation and other signaling pathways in HTLV-1-transformed cells. , and CREB were purchased from Cell Signaling Technology. Phospho-specific anti-TAK1 (Thr-187) and anti-TAB1 (Ser-438) antibodies are described previously (12, 18). Antibody against TAB3 was generat...

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Section: Discussionsupporting

confidence: 93%

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

Suzuki

Singhirunnusorn

Mori

et al. 2007

Journal of Biological Chemistry

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“…Likewise, the loss of TAK1 is phenotypically similar to the loss of IKK␤. The role of TAK1 in Tax-induced NF-B activation has been controversial (7,35). The present results are in agreement with those of Wu and Sun (35) in showing the importance of TAK1 and IKK␤ in achieving optimal Tax-mediated IKK activation.…”

Section: Tax-irs Is Not Executed Via the Alternative Nf-b Pathwaysupporting

confidence: 91%

HTLV-1 Tax-Induced Rapid Senescence Is Driven by the Transcriptional Activity of NF-κB and Depends on Chronically Activated IKKα and p65/RelA

Zhi

DeBiaso

et al. 2012

J Virol

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The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-κB pathways and is thought to promote cell proliferation and transformation via NF-κB activation. We showed recently that hyperactivation of NF-κB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-κB activation by expression of I-κBα superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-κB. Knockdown of IKKγ, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-κB pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKKα in the transcriptional activity of NF-κB, IKKα deficiency drastically decreased NF-κB trans -activation by Tax, although it only modestly reduced Tax-mediated I-κBα degradation and NF-κB nuclear localization. In contrast, although IKKβ knockdown attenuated Tax-induced NF-κB transcriptional activation, the residual NF-κB activation in IKKβ-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKKα and IKKβ knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKKγ, helps recruit NIK and TAK1 for IKKα and IKKβ activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-κB pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-κB, which depends on activated IKKα and p65/RelA.

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“…However, the conclusions by Gohda et al were derived from a single experiment, an NF-B luciferase assay with siRNA-mediated knockdown of Ubc13 in 293T cells (15). It is unclear to us why our results are inconsistent with the findings by Gohda et al Our findings in four different cell types, 293T, Ubc13 Ϫ/Ϫ MEFs, Jurkat, and C8166 cells, using a variety of different assays, consistently support a role for Ubc13 in Tax-mediated NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

“…Tax activates the IKK complex by directly interacting with NEMO, an event that is central to the activation of both canonical and noncanonical pathways by Tax (23,30). Although the exact mechanism by which Tax activates IKK remains unclear, Tax may recruit upstream kinases, such as transforming growth factor ␤-activated kinase 1 (15,51,52). In addition to providing an intracellular stimulus for IKK activation, Tax also opposes IKK-negative regulatory mechanisms, such as that exerted by the phosphatase PP2A (11).…”

mentioning

confidence: 99%

The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation

Shembade

Harhaj

Yamamoto

et al. 2007

J Virol

105

138

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Ubiquitination of the human T-cell leukemia virus 1 Tax oncoprotein provides an important regulatory mechanism that promotes the Tax-mediated activation of NF-B. However, the type of polyubiquitin chain linkages and the host factors that are required for Tax ubiquitination have not been identified. Here, we demonstrate that Tax polyubiquitin chains are composed predominantly of lysine 63-linked chains. Furthermore, the ubiquitination of Tax is critically dependent on the E2 ubiquitin-conjugating enzyme Ubc13. Tax interacts with Ubc13, and small interfering RNA-mediated knockdown of Ubc13 expression abrogates Tax ubiquitination and the activation of NF-B. Mouse fibroblasts lacking Ubc13 exhibit impaired Tax activation of NF-B despite normal tumor necrosis factor-and interleukin-1-mediated NF-B activation. Finally, the interaction of Tax with NEMO is disrupted in the absence of Tax ubiquitination and Ubc13 expression, suggesting that Tax ubiquitination is critical for NEMO binding. Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-B activation.

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HTLV-1 Tax-induced NFκB activation is independent of Lys-63-linked-type polyubiquitination

Cited by 22 publications

References 25 publications

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

HTLV-1 Tax-Induced Rapid Senescence Is Driven by the Transcriptional Activity of NF-κB and Depends on Chronically Activated IKKα and p65/RelA

The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation

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