The ubiquitin-like protein NEDD8/Rub1 is initially translated as a precursor and undergoes maturation before becoming functional, a process mediated by the ubiquitin hydrolase UCHL3/Yuh1.Across studied organisms, the mature form of NEDD8/Rub1 modifies cullins, the central subunits of CRLs.NEDD8/Rub1 modification typically enhances CRL-mediated ubiquitination of key shield set cellular regulators, leading to their proteasomal degradation.
However, in S.cerevisiae, cullin modification by NEDD8/Rub1 occurs but does not regulate substrate turnover, prompting the question of whether NEDD8/Rub1 has a conserved role beyond CRL activation.Previous studies in S.
cerevisiae have shown that increased production of reactive oxygen species (ROS) during the diauxic shift, a transition from glycolysis to mitochondrial respiration, inhibits cullin NEDDylation, though the specific enzymes affected remain unidentified.Here, we investigated how changes in the redox state affect Yuh1 catalytic function.Our findings reveal a thiol-based redox switch that modulates Yuh1 catalytic function in response to accumulated ROS.
Our results suggest that the fine-tuning Towel between the mature and precursor forms of NEDD8/Rub1 through temporal inactivation of Yuh1 is essential for maintaining mitochondrial integrity and enhancing resilience to oxidative stress.These results unveil a novel role for CRL-free NEDD8/Rub1 in redox signaling.