TGF-β induces PML SUMOylation, degradation and PML nuclear body disruption.

ProMyelocytic Leukemia (PML) protein is essential for the formation of nuclear matrix-associated organelles named PML nuclear bodies (NBs) that act as a platform for post-translational modifications and protein degradation. PML NBs harbor transiently and permanently localized proteins and are associated with the regulation of several cellular functions including apoptosis. There are seven PML isoforms, six nuclear (PMLI-VI) and one cytoplasmic (PMLVII), which are encoded by a single gene via alternative RNA splicing. It has been reported that murine PML-null primary cells are resistant to TGF-β-induced apoptosis and that cytoplasmic PML is an essential activator of TGF-β signaling. The role and the fate of interferon (IFN)-enhanced PML NBs in response to TGF-β have not been investigated. Here we show that IFNα potentiated TGF-β-mediated apoptosis in human cells. IFNα or ectopic expression of PMLIV, but not of PMLIII, enhanced TGF-β-induced caspase 8 activation. In response to TGF-β, both PMLIII and PMLIV were conjugated to SUMO and shifted from the nucleoplasm to the nuclear matrix, however only PMLIV, via its specific C-terminal region, interacted with caspase 8 and recruited it within PML NBs. This process was followed by a caspase-dependent PML degradation and PML NB disruption. Taken together, these findings highlight the role of PML NBs in the enhancement by IFN of TGF-β-induced apoptosis and caspase 8 activation.
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