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

Abstract

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. Here, we describe a new family of bacterial DUBs that is structurally related to eukaryotic Josephins, 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 the shift and found them conserved in other clippases, including one highly specific for M1-linked ubiquitin chains. This new enzyme class has great potential as tools to study the ubiquitin system, in particular aspects involving branched chains.