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

08:00 EDT 3rd July 2019 | BioPortfolio

Summary of "The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability."

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 subunit and functions as a cofactor for NF-κB-dependent transactivation. We thus hypothesized that the dissociation of p65-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-κB-signaling and genomic instability. Here we report that the inhibition of Stathmin expression by the retroviral latency protein, p30, or knockdown with siRNA-stathmin, dampens Tax-mediated NF-κB transactivation and counters Tax-induced genomic instability and cytotoxicity. The Tax-G148V mutant, defective for NF-κB activation, exhibited reduced p65-Stathmin binding and diminished genomic instability and cytotoxicity. Dominant-negative inhibitors of NF-κB also prevented Tax-induced multinucleation and apoptosis. Moreover, cell clones containing the infectious HTLV-1 ACH. p30 mutant provirus, impaired for p30 production, exhibited increased multinucleation and the accumulation of cytoplasmic tubulin aggregates following nocodozole-treatment. These findings allude to a mechanism whereby NF-κB-signaling regulates tubulin dynamics and mitotic instability through the modulation of p65-Stathmin/Op-18 interactions, and support the notion that p30 enhances the survival of Tax-expressing HTLV-1-transformed cells.

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This article was published in the following journal.

Name: Virology
ISSN: 1096-0341
Pages: 83-101

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