Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome

Kfoury, Youmna; Nasr, Rihab; Favre-Bonvin, Arnaud; El-Sabban, Marwan; Renault, Noémie; Giron, M-L; Setterblad, Niclas; Hajj, Hiba El; Chiari, Estelle; Mikati, A G; Hermine, Olivier; Saı̈b, Ali; Thé, Hugues de; Pique, Claudine; Bazarbachi, Ali

doi:10.1038/sj.onc.1210804

Cited by 68 publications

(106 citation statements)

References 20 publications

(35 reference statements)

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“…36,53 In the cytoplasm, Tax also concentrates in perinuclear speckles that localize near the centrosome, the microtubule-organizing center, and the cis-Golgi. 54,56,57 Recently, K63-polyubiquitinated Tax was shown to recruit inhibitor B kinase complex to this perinuclear compartment, supporting a model in which Tax activates inhibitor B kinase in a centrosome-dependent manner. 56 However, preliminary data suggest that Tax itself may not need to be ubiquitinated to stabilize the p13 protein.…”

mentioning

confidence: 97%

“…54,56,57 Recently, K63-polyubiquitinated Tax was shown to recruit inhibitor B kinase complex to this perinuclear compartment, supporting a model in which Tax activates inhibitor B kinase in a centrosome-dependent manner. 56 However, preliminary data suggest that Tax itself may not need to be ubiquitinated to stabilize the p13 protein. We found that the Tax mutant M22, which has been shown to be poorly ubiquitinated, is still capable of stabilizing p13 (data not shown).…”

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confidence: 97%

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Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Andresen

Pise-Masison

Sinha-Datta

et al. 2011

Blood

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IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) 1-3 and the neurologic disease HTLV-1-associated myelopathy/tropical spastic paresis (HAM/TSP). 4,5 In addition to the Gag, Pol, and Env proteins, HTLV-1 encodes through alternative splicing mRNAs for at least 7 additional viral proteins. The 2 essential positive regulators of HTLV-1 replication, the Tax and Rex proteins, are encoded by a unique, double-spliced mRNA and are expressed through ribosomal leaky scanning in orf-III and orf-IV, respectively. 6 Tax is an enhancer of viral transcription by its interaction with CREB/ATF, CBP/p300, and the Tax response element (TRE) located within the viral promoter. 7 In addition, Tax has been reported to interact with more than 100 different cellular proteins that affect gene expression, cell signaling, and proliferation. 8 Tax is also thought to be a promoter of T-cell transformation, because Tax expression immortalizes T cells in vitro and induces tumors in transgenic animals. 8,9 Rex interacts with a viral mRNA secondary structure, designated Rex responsive element (RxRE) located at the 3Ј-long terminal repeat (3Ј-LTR). Rex controls viral production by regulating the transport of unspliced and incompletely spliced viral mRNAs from the nucleus to the cytoplasm. 10 HTLV-1 also encodes 2 negative regulators of viral expression. The first, the p30 protein, is encoded by orf-II, interacts with tax/rex mRNA, and retains it in the nucleus. 11,12 At low concentrations, p30 also represses HTLV-1 LTR-driven transcription, whereas at high concentrations, 13,14 it activates transcription. The second negative regulator of HTLV-1 expression is the HTLV-1 basic zipper factor (HBZ) that is encoded by the antisense strand of the HTLV-1 genome. 15,16 HBZ interacts with CREB and CBP/p300, thereby blocking Tax-dependent transcription and viral expression. 17,18 HBZ also inhibits the activity of JunB and c-Jun by sequestering them in transcriptional inactive nuclear bodies and affects activating protein 1 (AP-1)-dependent cellular and viral transcription. 19,20 More recently, the HBZ antisense mRNA has been shown to induce T-cell proliferation. 21,22 p13 23,24 is a mitochondrial protein encoded by a distinct, singly spliced mRNA from orf-II. It accumulates in the inner membrane of the mitochondria and modulates K ϩ permeability and reactive oxygen species, thereby altering the morphology and function of mitochondria. [25][26][27] Evidence of p13 expression in HTLV-1-infected cells is indirect, because only the presence of mRNA has been demonstrated in both in vitro and ex vivo studies. [28][29][30] orf -II appears to be dispensable for viral infection and transformation of T cells in vitro; however, its requirement in HTLV-1 infection of rabbits remains uncertain because the mutation introduced into the HTLV-1 molecular clone to ablate p13 also affected the HBZ gene. [31][32][33] Furthermore, the p13 protein has been reported to suppress cell growth in vitro, tumorigeni...

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confidence: 97%

mentioning

confidence: 97%

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Andresen

Pise-Masison

Sinha-Datta

et al. 2011

Blood

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“…11,17,18 To investigate whether a unique molecule or distinct TAX AND NEMO DYNAMIC SHUTTLING 191 BLOOD, 6 JANUARY 2011 ⅐ VOLUME 117, NUMBER 1…”

Section: Tax Dynamic Trafficking Between Nuclear Bodies and Centrosomementioning

confidence: 99%

“…As a consequence, IB is phosphorylated, ubiquitylated, and degraded by the proteasome, and the NF-B complex translocates to the nucleus. 11 On the other hand, Tax SUMOylation is involved in the formation of Tax nuclear bodies and the recruitment of RelA to these bodies resulting in complete transcriptional activation. 17,18 Finally, K-48 ubiquitylation targets Tax for proteasomal degradation in the nucleoplasm.…”

mentioning

confidence: 99%

Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome

Kfoury

Setterblad

El-Sabban

et al. 2011

Blood

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The human T-lymphotropic virus type I oncoprotein Tax is critical for T-cell transformation, acting mainly through nuclear factor kappa B essential modulator (NEMO) binding and subsequent nuclear factor-B activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and small ubiquitin-like modifier (SUMO)ylation, which are both necessary for complete transcriptional activation. Using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome, depending on its posttranslational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. IntroductionTax, the viral oncoprotein encoded by the pX region of the human T-lymphotropic virus type I (HTLV-I) genome is a key player in the pathogenesis of HTLV-I-associated diseases, mainly adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLVassociated myelopathy. Tax deregulates the cellular machinery at multiple levels leading to the transformation of HTLV-I-infected T lymphocytes, predominantly through the activation of the nuclear factor-B (NF-B) pathway, which regulates key genes implicated in inflammation, apoptosis, and oncogenesis. 1,2 A corner stone in this NF-B activation is Tax binding to the regulatory subunit of the IB kinase (IKK) complex, IKK␥ (also known as NEMO). 3,4 Tax binding to NEMO phosphorylates both IKK␣ and IKK␤ leading to the formation of the IKK complex that phosphorylates the NF-B inhibitors IBs. This leads to the nuclear translocation of the active NF-B dimers and to transcriptional activation of target genes. 5 Tax/NEMO binding can also induce the IKK␣-dependent processing of the NF-B p100 precursor protein to its active p52 form. 6 Tax displays a dual nuclear and cytoplasmic localization with functions that are essential for cellular transformation in each compartment. 7,8 In the nucleus, Tax is predominantly located in RelA-enriched nuclear bodies. 9 In the cytoplasm, a major fraction of Tax lays in perinuclear hotspots colocalizing with the centrosome or microtubule organizing center in close association with the cis-Golgi compartment. 10,11 Posttranslational modification of proteins regulates protein functions by modifying their subcellular localization, stability, and/or network of interaction. We and others have described different forms of Tax posttranslational modifications including phosphorylation, 12,13 acetylation, 14 ubiquitylation, and small ubiquitin-like modifier (SUMO)ylation, 15,16 all of which are implicated in Tax-mediated activation of gene expression. Indeed, we showed that Tax is differentially ubiquitylated by either K-48 ubiquitin...

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“…24 For example, K63-ubiquitinylated Tax, which maintains permanent NF-κB activation, localizes to the centrosome; however, little is known about the centrosome localization of K63-linked polyubiquitinated proteins. 27 The roles of polyubiquitin chains linked through K6, K11, K27, K29, or K33 are poorly understood. 23 In this study, we investigated the mechanism of centrosome maturation.…”

Section: Introductionmentioning

confidence: 99%

Centrosomes at M phase act as a scaffold for the accumulation of intracellular ubiquitinated proteins

2014

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Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome

Cited by 68 publications

References 20 publications

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome

Centrosomes at M phase act as a scaffold for the accumulation of intracellular ubiquitinated proteins

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