Stimulation of IKK‐γ oligomerization by the human T‐cell leukemia virus oncoprotein Tax

Huang, Guojin; Zhang, Zhi Qing; Jin, Dong Yan

doi:10.1016/s0014-5793(02)03590-1

Cited by 29 publications

(35 citation statements)

References 45 publications

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“…These results reduce the size of the minimal oligomerization domain to 87 residues (amino acids 251-337). Our observation that fulllength NEMO (1) and either CC2-LZ or the isolated CC2 subdomain (this report) all form trimeric oligomers is in agreement with other studies (7,20). Tegethoff et al (21) proposed that the minimal oligomerization domain has a tetrameric structure.…”

Section: Role Of C-terminal Subdomains In Nemo Oligomerization-supporting

confidence: 93%

“…In vitro cross-linking experiments with the non-cleavable amine-reactive bis(sulfosuccinimidyl)suberate cross-linker established that pure recombinant NEMO autoassociates in dimers and trimers (20). Using a very similar amine-reactive cross-linking agent, ethylene glycol-bissuccinimidylsuccinate, Rothwarf et al (7) also found dimeric and trimeric forms of recombinant NEMO.…”

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confidence: 99%

“…Indeed, IKK can be activated by the enforced oligomerization of NEMO through the fusion with the FKBP12 polypeptide (17,18) or through oligomerization of the equine herpes virus-2 vCLAP protein, a NEMO-binding protein (19). In addition, the binding of Tax, a well known NF-B activator, to NEMO also results in its oligomerization (20).…”

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confidence: 99%

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The Trimerization Domain of Nemo Is Composed of the Interacting C-terminal CC2 and LZ Coiled-coil Subdomains

Agou

Traincard

Vinolo

et al. 2004

Journal of Biological Chemistry

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NEMO (NF-B essential modulator) plays a key role in the canonical NF-B pathway as the scaffold/regulatory component of the I B kinase (IKK) complex. The selfassociation of NEMO involves the C-terminal halves of the polypeptide chains containing two putative coiledcoil motifs (a CC2 and a LZ leucine zipper), a prolinerich region, and a ZF zinc finger motif. Using purified truncation mutants, we showed that the minimal oligomerization domain of NEMO is the CC2-LZ segment and that both CC2 and LZ subdomains are necessary to restore the LPS-dependent activation of the NF-B pathway in a NEMO-deficient cell line. We confirmed the association of the oligomerization domain in a trimer and investigated the specific role of CC2 and LZ subdomains in the building of the oligomer. Whereas a recombinant CC2-LZ polypeptide self-associated into a trimer with an association constant close to that of the wildtype protein, the isolated CC2 and LZ peptides, respectively, formed trimers and dimers with weaker association constants. Upon mixing, isolated CC2 and LZ peptides associated to form a stable hetero-hexamer as shown by gel filtration and fluorescence anisotropy experiments. We propose a structural model for the organization of the oligomerization domain of activated NEMO in which three C-terminal domains associate into a pseudo-hexamer forming a six-helix bundle. This model is discussed in relation to the mechanism of activation of the IKK complex by upstream activators.The NF-B signaling pathway plays a central role in the regulation of gene expression pertaining to inflammation, the immune response, oncogenesis, and apoptosis (1-5). In this canonical pathway, pro-inflammatory stimuli promote NF-B activation via phosphorylation of I B inhibitors by the kinases of the IKK 1 complex. This phosphorylation is in turn followed by ubiquitination and degradation of I B by the proteasome, allowing the NF-B transcription factors to enter the nucleus and to activate their target genes (4).The IKK complex contains two protein kinases, IKK-␣ and IKK-␤, and a structural/regulatory subunit called NEMO (NF-B essential modulator) or IKK-␥ (6 -8). NEMO is the key regulator of the NF-B pathway as genetic inactivation abolishes signaling in response to several extracellular stimuli (6, 9, 10). The activation of IKK-␤ is mediated through the trans-phosphorylation between IKK kinases (11). The mechanism by which NEMO is activated remains unclear and several factors have been proposed to be involved, including phosphorylation (12) and ubiquitination (13). Indeed, the de-ubiquitinating enzyme CYLD negatively regulates NF-B activation by specific tumor-necrosis factor receptors (14, 15) and was recently shown to 16). Converging evidence suggests that NEMO oligomerization plays a crucial role in the activation of the IKK complex. Indeed, IKK can be activated by the enforced oligomerization of NEMO through the fusion with the FKBP12 polypeptide (17, 18) or through oligomerization of the equine herpes virus-2 vCLAP protein, a NEMO-binding protein (19...

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Section: Role Of C-terminal Subdomains In Nemo Oligomerization-supporting

confidence: 93%

mentioning

confidence: 99%

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The Trimerization Domain of Nemo Is Composed of the Interacting C-terminal CC2 and LZ Coiled-coil Subdomains

Agou

Traincard

Vinolo

et al. 2004

Journal of Biological Chemistry

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“…Forced oligomerization of IKK␥ by fusion with the FKBP12 polypeptide leads to NF-B activation and the redistribution of the IKK subunits from uniform to punctate cytoplasmic staining (32). Tax also promotes the oligomerization of IKK␥ through a direct interaction (33). Thus, Tax likely triggers the oligomerization of IKK␥, through an undefined mechanism, leading to the oligomerization of associated IKKs and the redistribution to the perinuclear hot spots discovered in the present study.…”

Section: Discussionsupporting

confidence: 56%

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

Harhaj

Sun

Harhaj

2007

Journal of Biological Chemistry

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Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia. HTLV-1 encodes a trans-activating protein, Tax, which is largely responsible for the oncogenic properties of the virus. Tax promotes T cell transformation by deregulating the activity of various cellular factors, including the transcription factor NF-B. Tax activates the I B kinase (IKK) via physical interaction with the regulatory subunit, IKK␥, although it is unknown precisely how Tax activates the IKK complex. Here we show that Tax modulates the cellular localization of the IKK complex. The IKKs relocalize from a broad distribution in the cytoplasm to concentrated perinuclear "hot spots" in both HTLV-1-transformed lines and in Tax-expressing Jurkat cells. Relocalization of IKK is not observed with Tax mutants unable to activate NF-B, suggesting that only activated forms of IKK are relocalized. However, relocalization of IKK is strictly dependent on Tax expression because it does not occur in ATL cell lines that lack Tax expression or in Jurkat cells treated with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, IKK␥ is required for redistribution because cells lacking IKK␥ were unable to relocalize IKK␣ upon expression of Tax. We also find that Tax ubiquitination likely regulates IKK relocalization because mutation of three critical lysine residues in Tax renders it unable to relocalize IKK and activate the canonical and noncanonical NF-B pathways. Finally, we have observed that the perinuclear IKK in Tax-expressing cells colocalizes with the Golgi, and disruption of Golgi with either nocodazole or brefeldin A leads to a redistribution of IKK to the cytoplasm. Together, these results demonstrate that Tax induces relocalization of the IKK complex in a ubiquitin-dependent manner, and dynamic changes in the subcellular localization of the IKK complex may be critical for Tax function.The human T cell leukemia virus type I (HTLV-1) 3 is associated with adult T cell leukemia (ATL), an aggressive malignancy of CD4 ϩ T cells, and a neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (1). The HTLV-1 genome encodes a regulatory protein Tax in the pX region that plays a central role in HTLV-1-associated disease (2). Tax acts as a trans-activating protein that is critical for the expression of viral genes and also deregulates the expression of cellular genes. Tax regulates the expression of cellular genes by modulating signaling pathways such as NF-B, AP-1, CREB, and nuclear factor of activated T cells (3). Tax activation of NF-B is required for immortalization of T lymphocytes (4). Further, pharmacologic inhibition of NF-B leads to apoptosis of HTLV-1 transformed T cell lines and ATL cells (5).NF-B represents a family of transcription factors that regulate a wide variety of genes controlling cell survival, development, differentiation, and activation. NF-B family members include RelA (p65), c-Rel, RelB, p50, and p52, all of which contain a 300-amino acid Rel homology domain th...

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“…52 In fact, LRR, which contains three leucine residues repeated after each seven residues, does not bind directly with IKK-g, but it favors the homodimerization of Tax, which in turn induces IKK-g oligomerization and consequently, the catalytic activity of IKK. 52,53 In addition, Tax can constitutively activate IKK, by interacting with some upstream kinases such as MEKK1. 54 NIK also seems to play an important role in the IKK activation by Tax, since negative-dominant mutants of NIK inhibit NF-kB activation by Tax.…”

Section: Overview On Nf-jbmentioning

confidence: 99%

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

Kfoury

Nasr²,

Hermine³

et al. 2005

Cell Death Differ

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Stimulation of IKK‐γ oligomerization by the human T‐cell leukemia virus oncoprotein Tax

Cited by 29 publications

References 45 publications

The Trimerization Domain of Nemo Is Composed of the Interacting C-terminal CC2 and LZ Coiled-coil Subdomains

The Trimerization Domain of Nemo Is Composed of the Interacting C-terminal CC2 and LZ Coiled-coil Subdomains

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

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