E3 ligase enzymes are key regulators of many aspects of eukaryotic biology via the promotion of the ubiquitylation and subsequent degradation of proteins. There have been over 700 E3s identified within the ubiquitin system with diverse mechanisms of E3 ligase activity, however, significantly less have been identified for ubiquitin-like proteins. Recently developed activity-based probes allowed for the identification of novel E3 ligase proteins involved in the ubiquitin system that carry out unconventional ubiquitylation. The development...