Protein secretion is a process of fundamental importance for bacterial pathogenesis. Whether they deliver toxins or directly inject effector proteins into the cytoplasm of host cells, bacterial protein secretion systems play a central role in modulating eukaryotic cell functions. Legionella pneumophila are Gram-negative bacteria that are found ubiquitously in soil and freshwater environments. Once inhaled by humans, Legionella infections can result in a severe form of pneumonia known as Legionnaires' disease. Legionella use a type IV secretion system to deliver effector proteins, and this mediates the establishment of a replicative niche in host cells. The goal of our research is to understand at the molecular level how Legionella subvert host cellular functions to accomplish their successful intracellular replication. To this end, the following research projects are currently in progress.
(1) Analysis of the structure and function of the type IV secretion apparatus.
There is essentially nothing known about the substrate transfer across eukaryotic and bacterial membranes that occurs via type IV secretion systems. Furthermore, the macromolecular structure of the type IV secretion apparatus is largely unknown. To address these questions, we are working towards the structural and functional analysis of the type IV secretion apparatus from Legionella.
(2) Analysis of effector proteins that translocate from Legionella to host cells.
We previously demonstrated that RalF is translocated by the type IV secretion system of Legionella into host cells and is required for the recruitment of host ARF proteins to Legionella-containing vacuoles. We also recently demonstrated that the effector LubX acts as an E3 ligase and targets another effector for proteasomal degradation within host cells. LubX is the first effector protein that has been shown to target and regulate another effector within host cells.
Fig. 1 Type IV apparatus localizes to bacterial poles (Green). |
Fig. 2 Discovery of metaeffector. |