Redox-driven control of Yuh1/UCHL3 impacts mitochondrial health via NEDD8/Rub1 pathway

The ubiquitin-like protein NEDD8/Rub1 undergoes processing by the enzyme Yuh1/UCHL3 to become functional. While the processed NEDD8/Rub1 modifies Cullin-RING E3 ligases (CRLs) among all studied organisms, its role in facilitating CRL-based substrate degradation is absent in S. cerevisiae . This prompts questions about NEDD8/Rub1 functionality if it does not activate CRLs universally. Previous studies revealed that increased production of reactive oxygen species (ROS) during the glycolysis to mitochondrial respiration transition inhibits cullin NEDDylation in S. cerevisiae , yet the specific affected enzymes remain unidentified. Here, we investigate how redox changes affect Yuh1 activity, revealing a thiol-based redox switch modulating its catalytic function in response to ROS. Temporal inactivation of Yuh1 fine-tunes NEDD8/Rub1 mature and precursor species, both crucial for maintaining mitochondrial integrity and enhancing oxidative stress resilience. These findings unveil a novel role for Rub1/NEDD8 beyond CRL activation, linking redox signaling to NEDD8/Rub1 pathways. Graphical abstract