SUMO2/3 modification of transcription-associated proteins controls cell viability in response to oxygen and glucose deprivation-mediated stress

Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a proteomic approach in P19 cells to identify specific SUMO targets responding to OGD and to investigate the potential that these targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and glucose (ROG), confirming the high dynamics of this modification. Since OGD is linked to brain ischemia, we have also studied cells differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell protective effect largely depending on their sumoylation, and that maintaining the sumoylation capacity of the coregulator NAB2 is also important to face OGD. Conversely, sumoylation of the pluripotency factor OCT4, which is sumoylated under OGD, and is a target of the SUMO protease SENP7 for desumoylation after ROG, seems to block its cell survival-promoting capacity. Thus, better outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected factors.