Plague bacteria inject infected host cells with a ubiquitin-chopping enzyme, according to Zhou and colleagues in a study on page 1327. The group shows that the virulence factor YopJ operates as a deubiquitinase to shut down multiple signaling pathways that would otherwise help trigger an inflammatory immune response.

Pathogenic Yersinia bacteria need the cysteine protease YopJ to kill infected macrophages and promote systemic infection in mice. YopJ's activity somehow inhibits pro-inflammatory NF-κB signaling. Previous work by others had shown that YopJ can catalyze the removal of the ubiquitin-like protein SUMO-1 from cellular proteins. That work proposed that YopJ might desumolyate upstream activators of NF-κB.

Here, the authors show that YopJ does not act as a SUMO-1 isopeptidase, but rather as a deubiquitinase. YopJ stripped the ubiquitin chains from the adaptor molecules TRAF2 and TRAF6, which need these modifications to help activate NF-κB signaling, and also from the NF-κB inhibitor protein IκB. Ubiquitination of IκB normally tags the inhibitor for proteasomal degradation, thus allowing NF-κB to move into the nucleus and activate inflammatory genes.

YopJ could clip ubiquitin molecues attached either by their lysine 63 residue (as on the TRAF proteins) or by their lysine 48 residue (as on IκB). YopJ's deubiquitinating “promiscuity,” the authors write, allows the bacteria to simultaneously shut off multiple routes of NF-κB activation and thus to avoid immune attack. YopJ-related proteins exist in a diverse variety of bacterial pathogens, indicating that encoding deubiquitinases may be a common immune evasion tactic.