A family of bacterial Josephin-like deubiquitinases with an irreversible cleavage mode

Many intracellular bacteria secrete deubiquitinase (DUB) effectors into eukaryotic host cells to keep the bacterial surface or the enclosing vesicle membrane free of ubiquitin marks. This study describes a family of DUBs from several bacterial genera, including Simkania, Parachlamydia, Burkholderia, and Pigmentiphaga, which is structurally related to eukaryotic Josephin-type DUBs but contains members that catalyze a unique destructive substrate deubiquitination. These ubiquitin C-terminal clippases (UCCs) cleave ubiquitin before the C-terminal diGly motif, thereby truncating the modifier and leaving a remnant on the substrate. By comparing the crystal structures of substrate-bound clippases and a closely related conventional DUB, we identified the factors causing this shift and found them to be conserved in other clippases, including one highly specific for M1-linked ubiquitin chains. This enzyme class has great potential to serve as tools for studying the ubiquitin system, particularly aspects involving branched chains.