Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein

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 Taxmediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLD216-331, 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.

Functional interactions with Pit-1 reorganize co-repressor complexes in the living cell nucleus

“…A pharmacological HDAC inhibitor disrupted these subnuclear bodies, suggesting that they are maintained by specific functional interactions (Downes et al, 2000). This concept is supported by the observation that the spherical co-repressor focal bodies are spatially distinct from several other subnuclear protein compartments (Ariumi et al, 2003;Downes et al, 2000;Wu et al, 2001). Using a quantitative imaging approach, we demonstrated that MAD-body formation by NCoR was directly related to expression level (Voss et al, 2004), indicating a highly regulated mechanism controlling focalbody formation or maintenance.…”

Nuclear Compartmentalization of N-CoR and Its Interactions with Steroid Receptors

“…For example, one of the pre-mRNA splicing factors, SC35, appears as 20 to 40 speckles per nucleus (67). The promyelocytic leukemia gene product controlling aspects of apoptosis, cell proliferation, and transcriptional regulation was found within distinct subnuclear bodies, termed promyelocytic leukemia (PML) nuclear bodies (PML-NBs) (3). Some corepressor complexes were localized in distinct subnuclear bodies line, MCF-7, were obtained from American Type Culture Collection (Manassas, VA).…”

Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1

“…In addition, PML has been shown to modulate Tax function in different contexts (7,41). However, previous findings on the colocalization of Tax with PML remain controversial.…”

“…However, previous findings on the colocalization of Tax with PML remain controversial. Although one group has suggested the residence of Tax in PML domains (7), others have also found that Tax and PML are separate (41). To clarify this issue, we costained Tax-expressing cells for Tax and PML.…”