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