Proteins containing ubiquitin-like (Ubl) domains not only bind to 26S proteasomes but also induce their activation

Significance Most protein degradation in eukaryotic cells is catalyzed by the 26S proteasome, which digests proteins marked for destruction by a chain of ubiquitin molecules. Typically, 26S proteasomes are present in cells as inactive particles that can become active when a ubiquitylated substrate binds. Proteasomes are usually viewed as containing a characteristic set of subunits, but, in cells, many important proteins associate transiently with proteasomes to deliver substrates or provide additional activities. Here, we show that a major class of proteasome-binding proteins that contain a ubiquitin-like (Ubl) domain can also enhance the 26S proteasome’s multiple enzymatic activities that are critical for protein degradation. Thus Ubl-containing proteins, in addition to their other functions, have this unexpected regulatory role.