Abstract
Post-translational protein regulation allows for fine-tuning of cellular functions and involves a wide range of modifications, including ubiquitin and ubiquitin-like modifiers (Ubls). The dynamic balance of Ubl conjugation and removal shapes the fates of target substrates, in turn modulating various cellular processes. The mechanistic aspects of Ubl pathways and their biological roles have been largely established in yeast, plants, and mammalian cells. However, these modifiers may be utilised differently in highly specialised and divergent organisms, such as parasitic protozoa. In this review, we explore how these parasites employ Ubls, in particular SUMO, NEDD8, ATG8, ATG12, URM1, and UFM1, to regulate their unconventional cellular physiology. We discuss emerging data that provide evidence of Ubl-mediated regulation of unique parasite-specific processes, as well as the distinctive features of Ubl pathways in parasitic protozoa. We also highlight the potential to leverage these essential regulators and their cognate enzymatic machinery for development of therapeutics to protect against the diseases caused by protozoan parasites.
Highlights
When Parasitic Protozoa Met ubiquitin-like modifiers (Ubls)Parasitic protozoa are a diverse polyphyletic group of unicellular eukaryotes that have adapted to live in the cells, tissues, or organs of host organisms [1]
Parasitic protozoa employ a variety of Ubls that are structurally conserved across eukaryotes as post-translational modifiers
small ubiquitin-related modifier (SUMO), neural precursor cell-expressed developmentally downregulated 8 (NEDD8), and ubiquitin-related modifier 1 (URM1) have been identified in all major lineages of these parasites, while ATG8, ATG12, and ubiquitin-fold modifier 1 (UFM1) are not uniformly present
Summary
Parasitic protozoa are a diverse polyphyletic group of unicellular eukaryotes that have adapted to live in the cells, tissues, or organs of host organisms [1]. Research into the functional aspects of ubiquitin and Ubl pathways has been accelerated by the development of activity-based probes [44,45,46] and inhibitors [47,48,49,50] that target modifier-specific enzymatic machinery with high specificity These chemical tools, often coupled with mass spectrometry and X-ray crystallography, enable the capture, identification, and structural and functional characterisation of enzymes mediating the Ubl cascades. Many experimental and computational techniques developed in model organisms are difficult to implement in parasitic protozoa due to striking deviations in their genomes, cellular processes, and regulatory mechanisms Another obstacle is the complexity of life cycles and environmental requirements of protozoan parasites, making many unsuitable for large-scale cultivation and recapitulation of the complete life cycle in the laboratory. We will highlight the distinguishing features of Ubl enzymatic machinery in these unusual organisms and the potential for Ubl pathways to be targeted by current and novel drugs against the diseases caused by parasitic protozoa
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