Thiol-based redox control of NEDD8 pathways

Crosstalk between thiol-based redox modifications and other PTMs has recently emerged as an important intracellular signaling mechanism. NEDD8/Rub1 is a highly conserved ubiquitin-like PTM that has been identified as a key regulator of cellular redox. Our main knowledge of NEDD8 came from studies of its function as an activator of Cullin–RING E3 ligases (CRLs) through modification of their central subunit, known as cullin. CRLs selectively ubiquitinate a large portion of proteins targeted for proteolysis by the 26S proteasome and have been linked to many aspects of tumorigenesis as they mediate the turnover of key cellular players.

We previously revealed extensive production of ROS upon the transition of S. cerevisiae cells from glycolysis to mitochondrial respiration (i.e., diauxic shift) as a checkpoint of cullin NEDDylation. We now confirmed that the thiol group of cysteine residues in certain NEDD8 cascade enzymes is susceptible to reversible thiol oxidation. Oxidation prevents the transfer of free NEDD8 to cullins, but does not interfere with the reversible hydrolysis, eventually, leading to the accumulation of cullin-free NEDD8 conjugates. The possible role/fate of the redox-based non-cullin NEDDylation will be discussed.