Insights into non-proteinaceous ubiquitination

Ubiquitination plays a key role in the regulation of numerous diverse cellular functions. This process involves the covalent attachment of ubiquitin to protein substrates by a cascade of enzymes. In recent years, various non-proteinaceous substrates of ubiquitination have been discovered, expanding the potential for the functions of ubiquitination beyond its conventional role as a post-translational modification. Here, we profile the non-proteinaceous substrates of ubiquitination reported to date, the enzymes that regulate these activities, and the mechanistic details of substrate modification. The biological functions linked to these modifications are discussed, and finally, we highlight the challenges hindering further progress in the identification and functional characterization of non-proteinaceous substrates of ubiquitination within cellular contexts.