Ubiquitin chain editing mechanisms on the mammalian proteasome

The 26S proteasome is now accepted as a versatile and active player for fine‐tuning the substrate degradation cycle rather than a passive degradation machinery as once thought. However, ubiquitin conjugate processing by the mammalian proteasome remains poorly understood, partly due to the lack of specific tools. We recently developed a small‐molecule inhibitor selectively targeting USP14, a major deubiquitinating enzyme on the proteasome. By employing this inhibitor, we revealed that ubiquitin chain processing on the proteasome is surprisingly sophisticated, discriminating very sensitively among substrates on the basis of diverse configurations and architectures of the ubiquitin conjugates. Our data suggest a dynamic engagement of Usp14 in recognizing and processing the chain in the context of proteasome.