Targeting One of its Own: Expanding Roles of Substrates of the Legionella Pneumophila Dot/Icm Type IV Secretion System

Facing the many host defense mechanisms at different stages of the infection, a pathogen needs to employ corresponding arsenals either to hijack host cellular processes for its own use or to thwart the attacks from the host. For numerous bacterial pathogens, one of the effective weapons is effector protein. Type IV protein secretion systems are associated with the virulence of many important pathogens such as Helicobacter pylori, Bartenella pertussis, Brucella spp., Coxiella burnetii, and Legionella pneumophila (Backert and Meyer, 2006). Although the structures of these transporters appear similar , their protein substrates differ drastically not only in functions but also in abundance. For example, despite extensive efforts, CagA is the only effector identified for the Cag system of H. pylori (Hatakeyama, 2008). On the other hand, there are at least 274 experimentally confirmed protein substrates of the L. pneumophila Dot/Icm system (Zhu et al., 2011). This count is close to 10% of the predicted genes in the L. Dot/Icm system arguably the most prolific protein transporter in term of the number of translocated substrates. Similar to effectors of other types of secretion systems, Dot/Icm substrates function to target various host cellular processes, such as vesicle trafficking, cell death, ubiquitination, lipid metabolism, and innate immunity, thus allowing the bio-genesis of an intracellular niche permissive for bacterial replication (Isberg et al., 2009; Hubber and Roy, 2010). To cope with the dynamic response from the host, bacterial pathogens can employ several strategies to achieve temporal regulation of the activity of their virulence factors. The most commonly used mechanism is to regulate expression of virulence factors at the transcriptional level in response to environmental cues present during different phases of infection. For example, many Legionella effector genes are induced when bacteria enter the post-exponential phase and are ready to infect (Bruggemann et al., 2006). The second is to control the translocation efficiency of effectors at post-translational level, which is exemplified by small RNA-mediated regulation of effec-tor transfer in Salmonella typhimurium (Padalon-Brauch et al., 2008). The third is to code for effectors capable of causing opposite cell biological effects to neutralize or reverse the effects caused by other effec-tors. In S. typhimurium, bacterial entry is induced by SopE, a guanine nucleotide exchange factor (GEF) for the Rho family of small GTPases, an activity that is antagonized by the GTPase activation protein (GAP) SopE. In this scenario, temporal control is achieved by the inherent differences in …