Abstract

Synopsis: It is generally assumed that degradation by the ubiquitin-proteasome pathway is regulated solely by ubiquitination. However, we recently found several novel cellular mechanism that regulate proteasome content and functional capacity. When proteasomes are inhibited pharmacologically or become stalled, they have a mechanism that prevents further binding of ubiquitin conjugates, and they stimulate production of new proteasomes by enhancing transcription of genes for all proteasome subunits. We also have found that proteasome capacity to degrade ubiquitin conjugates and misfolded aggregation-prone proteins in cells is enhanced by phosphorylation of a 19S regulatory subunit. In certain mouse or cellular models of neurodegenerative disease, the 26S proteasome’s capacity to degrade ubiquitinated proteins is impaired, but can be activated by pharmacological agents that promote proteasome phosphorylation and thus enhance the degradation of the toxic proteins.