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The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-?B p65RelA-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability.

ABSTRACT: Genomic instability is a hallmark of many cancers; however, the molecular etiology of chromosomal dysregulation is not well understood. The human T-cell leukemia virus type-1 (HTLV-1) oncoprotein Tax activates NF-?B-signaling and induces DNA-damage and aberrant chromosomal segregation through diverse mechanisms which contribute to viral carcinogenesis. Intriguingly, Stathmin/oncoprotein-18 (Op-18) depolymerizes tubulin and interacts with the p65RelA subunit and functions as a cofactor for NF-?B-dependent transactivation. We thus hypothesized that the dissociation of p65RelA-Stathmin/Op-18 complexes by Tax could lead to the catastrophic destabilization of microtubule (MT) spindle fibers during mitosis and provide a novel mechanistic link between NF-?B-signaling and genomic instability. Here we report that the inhibition of Stathmin expression by the retroviral latency protein, p30II, or knockdown with siRNA-stathmin, dampens Tax-mediated NF-?B transactivation and counters Tax-induced genomic instability and cytotoxicity. The Tax-G148V mutant, defective for NF-?B activation, exhibited reduced p65RelA-Stathmin binding and diminished genomic instability and cytotoxicity. Dominant-negative inhibitors of NF-?B also prevented Tax-induced multinucleation and apoptosis. Moreover, cell clones containing the infectious HTLV-1 ACH. p30II mutant provirus, impaired for p30II production, exhibited increased multinucleation and the accumulation of cytoplasmic tubulin aggregates following nocodozole-treatment. These findings allude to a mechanism whereby NF-?B-signaling regulates tubulin dynamics and mitotic instability through the modulation of p65RelA-Stathmin/Op-18 interactions, and support the notion that p30II enhances the survival of Tax-expressing HTLV-1-transformed cells.

SUBMITTER: Malu A

PROVIDER: S-EPMC6940561 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65<sup>RelA</sup>-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability.

Malu Aditi A Hutchison Tetiana T Yapindi Laçin L Smith Katie K Nelson Katherine K Bergeson Rachel R Pope Jordan J Romeo Megan M Harrod Carolyn C Ratner Lee L Van Lint Carine C Harrod Robert R

Virology 20190703

Genomic instability is a hallmark of many cancers; however, the molecular etiology of chromosomal dysregulation is not well understood. The human T-cell leukemia virus type-1 (HTLV-1) oncoprotein Tax activates NF-κB-signaling and induces DNA-damage and aberrant chromosomal segregation through diverse mechanisms which contribute to viral carcinogenesis. Intriguingly, Stathmin/oncoprotein-18 (Op-18) depolymerizes tubulin and interacts with the p65<sup>RelA</sup> subunit and functions as a cofactor ...[more]

PMID: 31299491

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Project description:BACKGROUND:Human T-cell leukemia virus type 1 (HTLV-1) infects primarily CD4+ T-lymphocytes and evoques severe diseases, predominantly Adult T-Cell Leukemia/ Lymphoma (ATL/L) and HTLV-1-associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF-?B) by Tax represents a hallmark of HTLV-1 driven cancer. RESULTS:Here we found that Tax mutants which are defective in NF-?B signaling showed diminished protein expression levels compared to Tax wildtype in T-cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF-?B signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK-?), IKK2-EE, rescued protein expression of the NF-?B defective Tax mutants M22 and K1-10R and even increased protein levels of Tax wildtype in various T-cell lines while Tax transcript levels were only slightly affected. Using several Tax expression constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12-O-Tetradecanoylphorbol-13-Acetate [TPA; Phorbol 12-myristate 13-acetate (PMA)]/ ionomycin, inducers of NF-?B and cytokine signaling, but not by tumor necrosis factor alpha (TNF-?). On the other hand, co-expression of Tax with a dominant negative inhibitor of ?B, I?B?-DN, or specific inhibition of IKK2 by the compound ACHP, led to a vast decrease in Tax protein levels to some extent independent of Tax transcripts in transiently transfected and Tax-transformed T-cells. Cycloheximide chase experiments revealed that co-expression of IKK2-EE prolongs the half-life of M22, and constant repression of NF-?B signaling by I?B?-DN strongly reduces protein stability of Tax wildtype suggesting that NF-?B activity is required for Tax protein stability. Finally, protein expression of Tax and M22 could be recovered by NH4Cl and PYR-41, inhibitors of the lysosome and the ubiquitin-activating enzyme E1, respectively. CONCLUSIONS:Together, these findings suggest that Tax's capability to induce NF-?B is critical for protein expression and stabilization of Tax itself. Overall, identification of this novel positive feedback loop between Tax and NF-?B in T-cells improves our understanding of Tax-driven transformation.

Dataset Information

The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-?B p65RelA-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability.

Publications

The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65<sup>RelA</sup>-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability.

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