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Secretion of antibacterial toxins by the bacterial type VII secretion system

The Type VII protein secretion system (T7SS) is found in mycobacteria and in many Gram-positive bacteria including the human pathogen Staphylococcus aureus. S. aureus encodes a single T7SS that is genetically diverse between strains. The S. aureus T7SS machinery is composed of four membrane proteins, EsaA, EssA, EssB and EssC, and two additional globular proteins EsxA and EsaB. Structural studies and comparison with the mycobacterial T7SS suggest that EssC, a member of the AAA+ ATPase superfamily, protein most likely forms the secretion pore. Some strains of S. aureus secrete a large nuclease toxin, EsaD, through the T7SS that is very potent, and highly active against chromosomal DNA. S. aureus protects itself from the action of the nuclease by producing an anti-toxin that binds tightly to the nuclease, blocking its activity. The nuclease also interacts with a specific chaperone that appears to target the nuclease-anti-toxin complex to the secretion machinery. During secretion by the T7SS, the anti-toxin is probably dissociated from the nuclease and remains inside the cell while the nuclease is secreted. Co-culture experiments indicates that the T7-dependent nuclease mediates competition between closely related S. aureus strains, which is likely to be important during colonization. Recently we have identified additional families of T7SS substrates that shows an unexpected structural organisation.One of these, TslA, has an unexpected domain rearrangement and is a phospholipase toxin with antibacterial activity. Two small proteins encoded at the tslA locus interact with TslA and facilitate its secretion by the T7SS. Also encoded at the tslA locus are multiple copies of an immunity protein, TilA. TilA which binds with high affinity to the lipase domain of TslA, blocking its activity. In our newest work we have started to study the ESX-4 T7SS of the opportunistic pathogen Mycobacterium abscessus, and have identified the first antibacterial toxin secreted by ESX-4.