Regulation of Substrate Processing by the Proteasome

The proteasome, a large protease, recognizes the target protein via its ubiquitin chain, unfolds the protein, removes the chain, and injects the unfolded protein through a narrow gated channel into the large interior chamber of its 28‐subunit core particle, where it will be degraded. Ubiquitin‐dependent protein degradation is essential for cells to survive many environmental stresses. Stress regulates the proteasome by changing its composition. In one example, we identified a response to deficient ubiquitin levels, or "ubiquitin stress." Ubiquitin stress does not upregulate proteasomes. Instead, ubiquitin stress alters proteasome composition. The gene encoding deubiquitinating enzyme Ubp6, which associates with the proteasome, is induced when ubiquitin levels fall. Enhanced loading of proteasomes with Ubp6 alters proteasome function. Ubp6 spares ubiquitin from proteasomal degradation via its deubiquitinating activity and probably also because of its capacity to inhibit the proteasome noncatalytically. This pathway, originally described in yeast, seems to function comparably in mammals. Ubp6 works in tension with the proteasome‐associated ubiquitin ligase Hul5. Ubp6 attenuates chains while Hul5 extends them. When Hul5 is missing, the proteasome works with impaired fidelity, perhaps because chain extension is needed to prolong the substrate's association with the proteasome. Unlike Ubp6, Hul5 is not induced by ubiquitin stress. Thus, when proteasomes are remodeled under some stress conditions, the ratio of Ubp6 to Hul5 is changed.