Listeria promotes systemic infection by targeting the host deubiquitinase CYLD

Listeria monocytogenes (Lm) is an intracellular pathogen that can cause life-threatening systemic infections. Internalin C (InlC) is a secreted factor required for full Lm virulence in systemic models of infection by mechanisms that remain unclear. Here, we show that InlC binds to CYLD, a host deubiquitinase and regulator of innate immunity. Structurally, we reveal the LRR domain of InlC binds the CAP-Gly2 domain of CYLD, independently of InlC's binding site for other host target proteins. Lm strains harboring amino acid substitutions in InlC that selectively disrupt binding to CYLD were examined. We demonstrate that after Lm accesses the host cytosol, InlC recruits CYLD to ubiquitin-positive bacteria. Recruitment of CYLD was dependent on the host E3 ligase RNF213, a major initiator of ubiquitin-mediated defenses. Furthermore, InlC-CYLD binding contributed to Lm virulence in mice. Together, these findings reveal how a secreted bacterial factor promotes the recruitment of a host deubiquitinase to cytosolic bacteria in response to ubiquitin-mediated defenses.