Microbial and acute phase stimuli disrupt promyelocytic leukemia tumor suppressive nodes

The promyelocytic leukaemia (PML) nuclear domain (PML-ND) is a nuclear sentinel for stress. Each PML-ND cradles a delicate scaffold of nucleoproteins, many of which can trigger the apoptotic death cascade if disrupted. Given their place in integrating stress and death, PML-NDs are obvious targets for excision from injury pathways by viruses and cancers. Viruses express proteins dedicated to silencing the PML-ND network and their failure can presage the suppression of viral replication. To understand how PML-NDs protect the cell from stress we must discover those damage pathways with which they connect. Such data will reveal the panoply of signal pathways lost in PML null cells and the extent to which infection and cancer can desensitise the cell to therapeutic intervention. A convenient and sensitive method with which to detect PML-ND stress induction is its biophysical reorganisation, as well defined dose responsive modifications of PML protein accompany damage recognition. The experiments that we present in this manuscript arose from an observation that lipid mediated transfection of plasmid DNA triggered a dramatic modification of PML-NDs that was identical to that seen following their recognition of DNA damage. In later experiments, we identified lipoprotein and IL-6 as potential mediators of this response. Collectively these data are the first to link an endotoxin component and IL-6 to the PML-ND compartment and, given the role of PML in cell fate, suggest increasing complexity at the interface of immunity and carcinogenesis.