HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains

Wang, Chong; Long, Wenying; Peng, Chao; Hu, Lin; Zhang, Qiong; Wu, Ailing; Zhang, Xiaoqing; Duan, Xiaotao; Wong, Catherine C. L.; Tanaka, Yuetsu; Xia, Zongping

doi:10.1371/journal.ppat.1005584

Cited by 21 publications

(25 citation statements)

References 69 publications

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“…Wang et al . also reported that K63‐linked polyubiquitin chains do not play a role in IKK activation by Tax, in direct contrast to multiple published reports on the importance of K63‐linked polyubiquitination in Tax‐NF‐κB signaling . It is highly improbable that Tax actually functions as an E3 ligase; however, additional studies are required to further examine this notion.…”

Section: Tax‐dependent Nf‐κb Activationmentioning

confidence: 94%

“…However, a recent study was unable to replicate these results by in vitro ubiquitination assays with recombinant Tax together with either UbcH5c, UbcH7, or Ubc13/Uev1A [79]. Wang et al [81] also reported that K63-linked polyubiquitin chains do not play a role in IKK activation by Tax, in direct contrast to multiple published reports on the importance of K63-linked polyubiquitination in Tax-NF-jB signaling [64,76,79]. It is highly improbable that Tax actually functions as an E3 ligase; however, additional studies are required to further examine this notion.…”

Section: Tax-dependent Nf-jb Activationmentioning

confidence: 98%

“…A recent study has claimed that Tax itself may function as an E3 ligase, which can synthesize free mixed‐linkage polyubiquitin chains that bind to NEMO and activate IKK . However, a recent study was unable to replicate these results by in vitro ubiquitination assays with recombinant Tax together with either UbcH5c, UbcH7, or Ubc13/Uev1A .…”

Section: Tax‐dependent Nf‐κb Activationmentioning

confidence: 99%

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NF‐κB signaling mechanisms in HTLV‐1‐induced adult T‐cell leukemia/lymphoma

Harhaj

Giam

2018

The FEBS Journal

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The human T‐cell leukemia virus type 1 (HTLV‐1) is a complex deltaretrovirus linked to adult T‐cell leukemia/lymphoma (ATLL), a fatal CD4 + malignancy in 3–5% of infected individuals. The HTLV‐1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV‐1 proviral integrations. Tax is a potent activator of NF‐κB, a key signaling pathway that is essential for the survival and proliferation of HTLV‐1‐infected T cells. However, constitutive NF‐κB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF‐κB‐induced senescence can selectively undergo clonal expansion after HTLV‐1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the tax gene or DNA hypermethylation of the 5′‐LTR. Despite the loss of Tax, NF‐κB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B‐cell receptor (T/BCR) and NF‐κB signaling pathways. In this review, we focus on the key events driving Tax‐dependent and ‐independent mechanisms of NF‐κB activation during the multistep process leading to ATLL.

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Section: Tax‐dependent Nf‐κb Activationmentioning

confidence: 94%

Section: Tax-dependent Nf-jb Activationmentioning

confidence: 98%

Section: Tax‐dependent Nf‐κb Activationmentioning

confidence: 99%

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NF‐κB signaling mechanisms in HTLV‐1‐induced adult T‐cell leukemia/lymphoma

Harhaj

Giam

2018

The FEBS Journal

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“…1). Interestingly, the human T-cell leukemia virus TAX oncoprotein catalyzes mixed K63-M1 pUb chains that instead juxtapose TAK1 and IKK complexes (33,34). Further studies are required to determine whether mixed K63-M1 pUb chains also signal downstream of LMP1.…”

mentioning

confidence: 99%

Epstein-Barr Virus LMP1-Mediated Oncogenicity

Wang

Jiang

Gewurz

2017

J Virol

124

104

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Epstein-Barr virus latent membrane protein 1 (LMP1) is expressed in multiple human malignancies, including nasopharyngeal carcinoma and Hodgkin and immunosuppression-associated lymphomas. LMP1 mimics CD40 signaling to activate multiple growth and survival pathways, in particular, NF-B. LMP1 has critical roles in Epstein-Barr virus (EBV)-driven B-cell transformation, and its expression causes fatal lymphoproliferative disease in immunosuppressed mice. Here, we review recent developments in studies of LMP1 signaling, LMP1-induced host dependency factors, mouse models of LMP1 lymphomagenesis, and anti-LMP1 immunotherapy approaches.

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“…Therefore, we envision two potential mechanisms of UBE4B regulation of Tax polyUb: 1) UBE4B functions as an E3 ligase for Tax and conjugates Tax with both K48and K63-linked polyUb chains, or 2) UBE4B functions as an E4 enzyme and extends K48and/or K63-linked polyUb chains primed by other E3 enzymes. Tax itself has been proposed to have E3 ligase activity [47], however we did not observe Tax polyUb chains in the absence of UBE4B in an in vitro Ub assay (Figure 9). It is curious that UBE4B promotes K48-linked polyubiquitination of Tax but does not appear to trigger its degradation.…”

Section: Knockdown Of Ube4b Triggered Apoptotic Cell Death and Diminimentioning

confidence: 53%

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation

Harhaj

Mohanty²,

Han

et al. 2020

Preprint

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify novel Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax.Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by coimmunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-B target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48-and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-B activation. conjugation factor UBE4B as a novel Tax binding protein that promotes both K48-and K63-linked polyubiquitination of Tax. Knockdown or knockout of UBE4B impairs Taxinduced NF-B activation and triggers apoptosis of HTLV-1 transformed cells. Therefore, UBE4B is an integral host factor that supports HTLV-1 Tax polyubiquitination, NF-B activation and cell survival.

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HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains

Cited by 21 publications

References 69 publications

NF‐κB signaling mechanisms in HTLV‐1‐induced adult T‐cell leukemia/lymphoma

NF‐κB signaling mechanisms in HTLV‐1‐induced adult T‐cell leukemia/lymphoma

Epstein-Barr Virus LMP1-Mediated Oncogenicity

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation

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