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Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein
Yasuo Ariumi1, Takeshi Ego, Atsushi Kaida
1Laboratory of Human Tumor Viruses, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
Several viruses target cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs) to induce their disruption, marked morphological changes in these structures or the relocation to PML-NB components to the cytoplasm of infected cells. PML conversely interferes with viral replication. We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding. Tax was identified within interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs; Tax expression did not affect PML-NB formation. Moreover, PML and CBP/p300 cooperatively activated Tax-mediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLDelta216-331, which fail to form PML-NBs, could also coactivate Tax-mediated trans-acting function but had no effect on retinoic acid receptor (RAR)- or p53-dependent gene expression. In contrast, SMRT (silencing mediator for retinoic acid and thyroid hormone receptors), a nuclear corepressor found within the matrix-associated deacetylase (MAD) nuclear body, relocalized into Tax-associated nuclear bodies upon coexpression with Tax. SMRT coactivated the trans-acting function of Tax through direct binding. Coexpression of SMRT and PML resulted in an additive activation of Tax trans-acting function. Thus, crosstalk between distinct nuclear bodies may control Tax function.
Insights
Promyelocytic leukemia (PML) protein coactivates human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein function. Nuclear bodies crosstalk influences Tax activity, revealing new therapeutic targets for HTLV-1 infection.
Area of Science:
- Virology
- Molecular Biology
- Cell Biology
Background:
- Viruses often disrupt cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs).
- PML protein can inhibit viral replication.
- The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein's interaction with nuclear structures is not fully understood.
Purpose of the Study:
- To investigate the role of PML and other nuclear bodies in HTLV-1 Tax oncoprotein function.
- To elucidate the mechanisms by which PML and associated factors modulate Tax activity.
- To explore the potential crosstalk between different nuclear bodies in regulating viral gene expression.
Main Methods:
- Immunofluorescence microscopy to visualize protein localization and nuclear body formation.
- Co-immunoprecipitation assays to assess protein-protein interactions.
- Reporter gene assays to measure HTLV-1 Long Terminal Repeat (LTR)-dependent gene expression.
Main Results:
- PML acts as a coactivator for HTLV-1 Tax, enhancing Tax-mediated gene expression without direct binding.
- Tax localizes to interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs, and does not disrupt PML-NB formation.
- PML mutants deficient in PML-NB formation still coactivate Tax function.
- The nuclear corepressor SMRT relocates to Tax-associated nuclear bodies and directly coactivates Tax function.
- Combined expression of PML and SMRT additively enhances Tax activity, suggesting nuclear body crosstalk.
Conclusions:
- PML protein is a crucial coactivator of HTLV-1 Tax oncoprotein.
- Crosstalk between distinct nuclear bodies, such as PML-NBs, IGCs/SBs, and MAD nuclear bodies, plays a significant role in controlling Tax function.
- These findings offer insights into viral hijacking of cellular machinery and potential therapeutic strategies against HTLV-1.