Subversion of Host Membrane Dynamics by the Legionella Dot/Icm Type IV Secretion System

Legionella species are Gram-negative ubiquitous environmental bacteria, which thrive in biofilms and parasitize protozoa. Employing an evolutionarily conserved mechanism, the opportunistic pathogens also replicate intracellularly in mammalian macrophages. This feature is a prerequisite for the pathogenicity of Legionella pneumophila, which causes the vast majority of clinical cases of a severe pneumonia, termed "Legionnaires' disease." In macrophages as well as in amoeba, L. pneumophila grows in a distinct membrane-bound compartment, the Legionella-containing vacuole (LCV). Formation of this replication-permissive pathogen compartment requires the bacterial Dot/Icm type IV secretion system (T4SS). Through the T4SS as many as 300 different "effector" proteins are injected into host cells, where they presumably subvert pivotal processes. Less than 40 Dot/Icm substrates have been characterized in detail to date, a number of which show unprecedented biological activities. Some of these effector proteins target host cell small GTPases, phosphoinositide lipids, the chelator phytate, the ubiquitination machinery, the retromer complex, the actin cytoskeleton, or the autophagy pathway. A recently discovered class of L. pneumophila effectors modulates the activity of other effectors and is termed "metaeffectors." Here, we summarize recent insight into the cellular functions and biochemical activities of L. pneumophila effectors and metaeffectors targeting the host's endocytic, retrograde, or autophagic pathways.