Legionella pneumophila inhibits immune signaling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N

The bacterial pathogen Legionella pneumophila modulates host immunity using effectors translocated by its Dot/Icm transporter to facilitate its intracellular replication. A number of these effectors employ diverse mechanisms to interfere with protein ubiquitination, a posttranslational modification essential for immunity. Here we found that L. pneumophila induces monoubiquitination of the E2 enzyme UBE2N by its Dot/Icm substrate MavC(Lpg2147). We demonstrate that MavC is a transglutaminase that catalyzes covalent linkage of ubiquitin to Lys(92) and Lys(94) of UBE2N via Gln(40). Similar to canonical transglutaminases, MavC possess deamidase activity that targets ubiquitin at Gln(40). We identified Cys(74) as the catalytic residue for both ubiquitination and deamidation activities. Furthermore, ubiquitination of UBE2N by MavC abolishes its activity in the formation of K(63)-type polyubiquitin chains, which dampens NFκB signaling in the initial phase of bacterial infection. Our results reveal an unprecedented mechanism of modulating host immunity by modifying a key ubiquitination enzyme by ubiquitin transglutamination.