title: Pupylation as a signal for proteasomal degradation in bacteria.
abstract: Posttranslational modifications in the form of covalently attached proteins like ubiquitin (Ub), were long considered an exclusive feature of eukaryotic organisms. The discovery of pupylation, the modification of lysine residues with a prokaryotic, ubiquitin-like protein (Pup), demonstrated that certain bacteria use a tagging pathway functionally related to ubiquitination in order to target proteins for proteasomal degradation. However, functional analogies do not translate into structural or mechanistic relatedness. Bacterial Pup, unlike eukaryotic Ub, does not adopt a β-grasp fold, but is intrinsically disordered. Furthermore, isopeptide bond formation in the pupylation process is carried out by enzymes evolutionary descendent from glutamine synthetases. While in eukaryotes, the proteasome is the main energy-dependent protein degradation machine, bacterial proteasomes exist in addition to other architecturally related degradation complexes, and their specific role along with the role of pupylation is still poorly understood. In Mycobacterium tuberculosis (Mtb), the Pup-proteasome system contributes to pathogenicity by supporting the bacterium's persistence within host macrophages. Here, we describe the mechanism and structural framework of pupylation and the targeting of pupylated proteins to the proteasome complex. Particular attention is given to the comparison of the bacterial Pup-proteasome system and the eukaryotic ubiquitin-proteasome system. Furthermore, the involvement of pupylation and proteasomal degradation in Mtb pathogenesis is discussed together with efforts to establish the Pup-proteasome system as a drug target. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
authors.affiliation: Max Planck Institute of Biochemistry, Department of Molecular Cell Biology, D-82152 Martinsried, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Striebel
authors.forename: Frank
authors.initials: F
authors.lastname: Imkamp
authors.forename: Dennis
authors.initials: D
authors.lastname: Özcelik
authors.forename: Eilika
authors.initials: E
authors.lastname: Weber-Ban
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000502:physiology; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D054875:Ubiquitination / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D021382:Protein Sorting Signals; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex
keywords: Mycobacterium tuberculosis; Post-translational modification; Prokaryotic ubiquitin-like protein Pup; Proteasome; Pupylation; Pup–proteasome pathway