The versatile bacterial type IV secretion systems

Abstract

Bacterial type IV secretion (T4S) systems are ancestrally related to conjugation systems. Present-day T4S systems can be subclassified into three groups: conjugation systems mediating the transfer of DNA and protein substrates through formation of stable mating junctions with recipient cells; DNA-uptake and -release systems that exchange DNA with the extracellular milieu; and effector translocator systems that deliver DNA and protein effector molecules to eukaryotic cells during the course of infection. The conjugation systems of Gram-negative bacteria are composed of the coupling protein homomultimer and two substructures encoded by the mating-pair-formation (Mpf) proteins, a protein complex spanning the cell envelope and the conjugative pilus (T-pilus). At the present time, investigators have identified the effector molecules of T4S systems for four pathogens: Agrobacterium tumefaciens, the causative agent of crown gall disease in plants; Helicobacter pylori, the causative agent of gastritis, peptic ulcers and gastric carcinomas in humans; Bordetella pertussis, the causative agent of whooping cough in humans; and Legionella pneumophila, the causative agent of Legionnaire's disease in humans. T4S system effector translocation alters a wide range of cellular processes to aid the infection process. For example, Agrobacterium tumefaciens delivers oncogenic T-DNA and protein effectors (VirE2, VirE3 and VirF) that interact with plant cellular factors to ensure delivery of the T-DNA to the nucleus and its integration into the plant genome. Helicobacter pylori uses the Cag T4S system to deliver CagA to mammalian cells where it is tyrosine phosphorylated by c-Src kinase. A complex network of interactions between CagA^P-Tyr and cellular factors (for example, c-Src, SHP-2, c-MET) and between non-phosphorylated CagA (Grb2, JAM, Z0-1) alters signalling pathways, ultimately triggering cellular proliferation and differentiation and the onset of cancer. The Bordetella pertussis Ptl system delivers its effector, the multisubunit pertussis toxin, to the extracellular milieu where, on contact with the mammalian cell membrane, the A subunit is internalized and exerts its effects by uncoupling G proteins from their receptors. In striking contrast to the other systems described in the review, the intracellular pathogen L. pneumophila uses the Dot/Icm T4S system to inject effectors (DotA, LidA, RalF) into the phagosome to control biogenesis of the replicative vacuoule and to modulate the activities of host factors involved in vesicle traffic.