Physical and in silico approaches identify DNA-PK in a Tax DNA-damage response interactome

Autophagy, a general homeostatic process for degradation of cytosolic proteins or organelles, has been reported to modulate the replication of many viruses. The role of autophagy in human T-cell leukemia virus type 1 (HTLV-1) replication has, however, been uncharacterized. Here, we report that HTLV-1 infection increases the accumulation of autophagosomes and that this accumulation increases HTLV-1 production. We found that the HTLV-1 Tax protein increases cellular autophagosome accumulation by acting to block the fusion of autophagosomes to lysosomes, preventing the degradation of the former by the latter. Interestingly, the inhibition of cellular autophagosome-lysosome fusion using bafilomycin A increased the stability of the Tax protein, suggesting that cellular degradation of Tax occurs in part through autophagy. Our current findings indicate that by interrupting the cell's autophagic process, Tax exerts a positive feedback on its own stability.

Section: Htlv-1 Infection Induced Autophagosome Accumulationmentioning

confidence: 99%

The Cellular Autophagy Pathway Modulates Human T-Cell Leukemia Virus Type 1 Replication

Tang

Chen

Klase

et al. 2013

“…DNA damage induced by Tax and other oncoproteins has been documented previously (11,31,37). Earlier, it was suggested that such oncogene-induced DNA damage may have occurred indirectly through accelerated G 1 cell cycle progression, which might in itself be mutagenic (11).…”

mentioning

confidence: 99%

Induction of Reactive Oxygen Species by Human T-Cell Leukemia Virus Type 1 Tax Correlates with DNA Damage and Expression of Cellular Senescence Marker

Kinjo

Ham-Terhune

Péloponèse

et al. 2010

Human T-cell leukemia virus type 1 (HTLV-1) Tax affects cellular genomic stability and senescence. As yet, the mechanism(s) for these events caused by Tax is incompletely understood. Here, we show that Tax expression in primary human cells induces reactive oxygen species (ROS), which elicits DNA damage and the expression of senescence marker. Treatment with a ROS scavenger or knockdown of Tax expression by small interfering RNA (siRNA) abrogated Tax-induced DNA damage and the expression of senescence marker. Our data suggest that ROS induction explains Tax-induced cellular DNA damage and cellular senescence.

“…The viral oncoprotein Tax increases the rate of transcription from the viral long terminal repeat (LTR) (12,15,23). In addition, Tax can modulate the expression or activities of numerous cellular proteins involved in cell proliferation and differentiation, cell cycle regulation, and DNA repair processes (11,30,36,37,42). The pleiotropic effects of Tax on cellular processes are required for its transforming and oncogenic capabilities and play a critical role in HTLV-induced cellular transformation (16,(39)(40)(41).…”

mentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication

Xie

Kesic²,

Yamamoto³

et al. 2009

Human T-cell leukemia virus (HTLV) regulatory protein, Rex, functions to increase the expression of the viral structural and enzymatic gene products. The phosphorylation of two serine residues (S151 and S153) at the C terminus is important for the function of HTLV-2 Rex (Rex-2). The Rex-2 phosphomimetic double mutant (S151D, S153D) is locked in a functionally active conformation. Since rex and tax genes overlap, Rex S151D and S153D mutants were found to alter the Tax oncoprotein coding sequence and transactivation activities. Therefore, additional Rex-2 mutants including P152D, A157D, S151Term, and S158Term were generated and characterized ("Term" indicates termination codon). All Rex-2 mutants and wild-type (wt) Rex-2 localized predominantly to the nucleus/nucleolus, but in contrast to the detection of phosphorylated and unphosphorylated forms of wt Rex-2 (p26 and p24), mutant proteins were detected as a single phosphoprotein species. We found that Rex P152D, A157D, and S158Term mutants are more functionally active than wt Rex-2 and that the Rex-2 C terminus and its specific phosphorylation state are required for stability and optimal expression. In the context of the provirus, the more active Rex mutants (A157D or S158Term) promoted increased viral protein production, increased viral infectious spread, and enhanced HTLV-2-mediated cellular proliferation. Moreover, these Rex mutant viruses replicated and persisted in inoculated rabbits despite higher antiviral antibody responses. Thus, we identified in Rex-2 a novel C-terminal inhibitory domain that regulates functional activity and is positively regulated through phosphorylation. The ability of this domain to modulate viral replication likely plays a key role in the infectious spread of the virus and in virus-induced cellular proliferation.