Structure(s) and mechanism of action of a novel bacterial secretion system

Lauber, Frédéric [UCL]

The T9SS is a novel secretion system exclusively found in Gram-negative bacteria of the phylum Bacteroidetes1. It is involved in a wide array of processes ranging from biofilm and S-layer formation to secretion of virulence factors in fish and avian pathogens. It is most notably associated with the human pathogen Porphyromonas gingivalis, the etiologic agent of chronic periodontitis, in which it is responsible for the secretion of the bacterium’s main virulence factors, so-called gingipains2. T9SS substrates are secreted in a two-step process, using the general secretory (Sec) pathway to cross the inner membrane before being translocated across the outer membrane (OM) via the T9SS. This second step is mediated by a specific recognition signal located in the C-terminus (the CTD) of T9SS substrates. The CTD is then proteolytically removed and substrates are either released or attached to the cell surface2,3. While all major components of the T9SS have been identified, little was known about the key aspects of the transport process across the OM, including how substrates are recognized and targeted to the secretion pore and, most importantly, the identity of the pore itself. We recently showed that the T9SS translocon is formed from the 36-strand transmembrane β- barrel protein SprA4. The barrel pore is capped on the extracellular end, but has a lateral opening to the external membrane surface. Structures of SprA bound to different T9SS components demonstrate that partner proteins control access to the lateral opening and to the periplasmic end of the pore, suggesting an alternating access mechanism in which the two ends of the protein conducting channel are open at different times. Our recent progress in understanding the molecular mechanism of the T9SS will be described.