RNF213 is a unique AAA+ ATPase and E3 ligase protein encoded by RNF213 gene which is a susceptibility factor for the cerebrovasculopathy Moyamoya. Recent studies have suggested that RNF213 plays a role in infection and inflammation, lipid metabolism, angiogenesis and even cancer. However, a clear mechanistic insight into its basal function and how this is altered in stressed states has not been explored in depth. We use IFNγ stress as an endogenous inducer of RNF213 and to further study its role in interferon and infection-specific stressed states. Using an acute knockdown system coupled with global proteomics approaches, we identify a novel role for RNF213 in the regulation of NRF2 signaling. Co-immunoprecipitation coupled mass spectrometry analysis of RNF213"s interaction partners reveals critical regulators of the replication, ribosomal biogenesis, transcription and splicing machinery. Furthermore, phosphoproteomic analysis of these conditions shows increased phosphorylation of critical regulators of the DNA damage response pathway. These findings indicate towards a role of RNF213 in the regulation of NRF2 signaling potentially via an altered DNA damage response initiated by perturbations of the replication and translation machinery complexes and interaction dynamics. RNF213-NRF2 regulation appears to be particularly important for its downstream functions in angiogenesis, infection and inflammation. Furthermore, it may also contribute towards novel aspects of RNF213"s role in cancer and senescence.