Figure 7. Putative model of dynamic FIH1 regulation by SUMOylation and deSUMOylation.

In low oxygen, nuclear FIH1 is targeted for SUMOylation by SUMO3, a process that is reversed by deSUMOylation via SENP3. This maintains HIF1A transcriptional activity. The consequence of FIH1 SUMOylation is the cytoplasmic recruitment of the ubiquitin ligase RNF4, which in turn promotes FIH1 ubiquitination and subsequent proteasomal degradation. In PE, lack of FIH1 deSUMOylation leads to accelerated FIH1 degradation thereby maintaining HIF1A transcriptional activity.