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

• Published in: Virology (New York, N.Y.) N.Y.), 2019-09, Vol.535, p.83
• Main Authors: Malu, Aditi, Hutchison, Tetiana, Yapindi, Laçin, Smith, Katie, Nelson, Katherine, Bergeson, Rachel, Pope, Jordan, Romeo, Megan, Harrod, Carolyn, Ratner, Lee, Van Lint, Carine, Harrod, Robert
• Format: Article
• Language: English
• Subjects: Gene Products, tax - metabolism; Genomic Instability; HEK293 Cells; Host-Pathogen Interactions; Human T-lymphotropic virus 1 - pathogenicity; Humans; Protein Binding; Protein Interaction Maps; Spindle Apparatus - metabolism; Stathmin - metabolism; Transcription Factor RelA - metabolism
• ISSN: 1096-0341
• DOI: 10.1016/j.virol.2019.07.003

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.