Prokaryotic ubiquitin-like protein (Pup) and the modification enzymes involved in attaching Pup to or removing it from target proteins present a fascinating example of convergent evolution with respect to eukaryotic ubiquitination. Like ubiquitin (Ub), Pup is a small protein that can be covalently attached to lysine side chains of cellular proteins, and like Ub, it can serve to recruit tagged proteins for proteasomal degradation. However, unlike Ub, Pup is conformationally highly dynamic, exhibits a different linkage connectivity to its target lysines, and its ligase belongs to a different class of enzymes than the E1/E2/E3 cascade of ubiquitination. A specific feature of actinobacteria (aside from sporadic cases in a few other lineages), pupylation appears to have evolved to provide an advantage to the bacteria under certain environmental stresses rather than act as a constitutive modification. For Mycobacterium tuberculosis, pupylation and the recruitment of pupylated substrates to the proteasome support persistence inside host macrophages during pathogenesis, rendering the Pup-proteasome system an attractive drug target. In this review, we consider the dynamic nature of Pup in relation to its function, discuss the reaction mechanisms of ligation to substrates and cleavage from pupylated substrates, and put them in context of the evolutionary history of this post-translational modification.
Keywords: Pup; depupylation; prokaryotic ubiquitin-like protein; proteasome; pupylation.
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