Ubiquitin-like modifiers and their deconjugating enzymes in medically important parasitic protozoa.

Protein modification by ubiquitin and ubiquitin-like proteins is one of the most complex and intensely studied mechanisms of posttranslational protein regulation in eukaryotes. Conjugation of the 76-amino-acid protein ubiquitin is first and foremost a signal for targeting proteins to the proteasome for degradation, but evidence that ubiquitin also plays diverse roles in the regulation of numerous biological pathways is building. In addition, there are many structurally related ubiquitin-like modifiers (Ubls) that utilize mechanistic pathways similar to those utilized by ubiquitin for conjugation to protein substrates and deconjugation. Despite similarities in structure between ubiquitin and other Ubls, modification by Ubls regulates such diverse cellular processes as transcriptional regulation, cell cycle control, and autophagy (see Kerscher et al. [22] for a review of Ubls and known functions). Ubiquitin has been identified in the majority of parasitic protozoa, but most Ubls in these organisms have not been characterized. Even less attention has been paid to the enzymes that regulate protein modification by ubiquitin or Ubls. The essential roles of ubiquitin and Ubls in both protein turnover and transcriptional regulation in other organisms suggest that ubiquitin and Ubl pathways should be explored to better understand basic parasite biology. For this reason, we have compiled a comprehensive list of homologs of known Ubls and Ubl-deconjugating enzymes in medically important protozoa. We also discuss potential differences and unique characteristics of Ubls and deconjugating enzymes in parasites compared to those in mammals and yeast such as Saccharomyces cerevisiae and Schizosaccharomyces pombe. Notably absent from this review are the enzymes that conjugate ubiquitin and Ubls to their substrates. Although conjugation machinery is also important to the pathway, the essential role of deconjugating enzymes in multiple biological pathways and recent publications describing the identification of inhibitors of these enzymes indicate that they may represent a potentially important class of protease drug targets in parasites. Therefore, we have chosen to focus this review on these enzymes and the modifiers they regulate. REGULATING THE REGULATORS: THE UBIQUITIN MODIFICATION PATHWAY