An oxidative switch regulates hierarchical proteasome disassembly

The accumulation of reactive oxygen species results in the modification of protein structures promoting their misfolding and aggregation. This in turn leads to activation of a cellular stress response, which promotes chaperone and antioxidant gene expression and attenuation of protein synthesis, in an attempt to overcome the oxidative damage. Yet, misfolded proteins that have undergone irreversible oxidative modification must be removed from the intracellular environment, mostly by the proteasome.

Based on our findings, we propose that an inherent cysteine “tweezer” within the 20S proteasome functions as an oxidative switch. Upon elevated oxidative conditions a disulfide bond between PSMB3 and PSMB7 is formed and promotes stepwise proteasome disassembly, which can serve as a protective measure to remove damaged proteasomes or perhaps enables a potential mechanism for damaged proteasomal subunits exchange. Using cryo-EM, cell biology and a novel family of proteasome inhibitors targeting this oxidative switch, we captured intermediate states underlining these transitions within the 20S proteasome.