Research ArticleBiochemistry

Regulation of the 26S Proteasome Complex During Oxidative Stress

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Science Signaling  07 Dec 2010:
Vol. 3, Issue 151, pp. ra88
DOI: 10.1126/scisignal.2001232

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Separation of Powers

The proteasome is a large, multicatalytic complex that degrades proteins in an ATP- and ubiquitin-dependent manner. The 26S proteasome is composed of the 20S catalytic core and the 19S regulatory particle. The 19S particle consists of two subcomplexes that constitute the base and lid structures around the catalytic core. When separated from the 26S proteasome, the 20S core degrades oxidized (nonubiquitinated) proteins. Oxidative stress results in the accumulation of damaged proteins in the cell, which are removed by proteasomes. Wang et al. used mass spectrometry to examine the effects of hydrogen peroxide (H2O2)–induced stress on the 26S proteasome in yeast. H2O2 triggered recruitment to the 19S particle of the proteasome-binding protein Ecm29 and disassembly of the 26S proteasome into its 20S and 19S constituents. Yeast strains deficient in Ecm29 did not exhibit 26S disassembly and were more sensitive to H2O2 than were wild-type cells. Indeed, an efficient response to H2O2 required disassembly of the 26S proteasome to generate sufficient amounts of free 20S core to degrade oxidized proteins. Similar results were obtained in experiments with a human cell line, which suggests that dissociation of the 26S proteasome in response to oxidative stress may be a conserved cellular response in eukaryotes.


The proteasome plays a pivotal role in the cellular response to oxidative stress. Here, we used biochemical and mass spectrometric methods to investigate structural changes in the 26S proteasomes from yeast and mammalian cells exposed to hydrogen peroxide (H2O2). Oxidative stress induced the dissociation of the 20S core particle from the 19S regulatory particle of the 26S proteasome, which resulted in loss of the activities of the 26S proteasome and accumulation of ubiquitinated proteins. H2O2 triggered the increased association of the proteasome-interacting protein Ecm29 with the purified 19S particle. Deletion of ECM29 in yeast cells prevented the disassembly of the 26S proteasome in response to oxidative stress, and ecm29 mutants were more sensitive to H2O2 than were wild-type cells, suggesting that separation of the 19S and 20S particles is important for cellular recovery from oxidative stress. The increased amount of free 20S core particles was required to degrade oxidized proteins. The Ecm29-dependent dissociation of the proteasome was independent of Yap1, a transcription factor that is critical for the oxidative stress response in yeast, and thus functions as a parallel defense pathway against H2O2-induced stress.

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