Abstract
Legionella pneumophila can cause Legionnaires’ disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). LCV formation is a complex process that involves a plethora of type IV-secreted effector proteins. The effector RidL binds the Vps29 retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. Here, we reveal that the 29-kDa N-terminal domain of RidL (RidL2–281) adopts a “foot-like” fold comprising a protruding β-hairpin at its “heel”. The deletion of the β-hairpin, the exchange to Glu of Ile170 in the β-hairpin, or Leu152 in Vps29 abolishes the interaction in eukaryotic cells and in vitro. RidL2–281 or RidL displace the Rab7 GTPase-activating protein (GAP) TBC1D5 from the retromer and LCVs, respectively, and TBC1D5 promotes the intracellular growth of L. pneumophila. Thus, the hydrophobic β-hairpin of RidL is critical for binding of the L. pneumophila effector to the Vps29 retromer subunit and displacement of the regulator TBC1D5.
Highlights
Legionella pneumophila can cause Legionnaires’ disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV)
The retromer binds the cytoplasmic part of transmembrane cargo receptors, followed by the interaction with sorting nexins (SNXs), and several accessory proteins participate in retromermediated sorting, tubule elongation and stabilization, and vesicle fission and transport[13,14,22,28]
Since the mutation Vps29L152E abolishes the interaction with host TBC1D543, we further investigated this site for potential binding of RidL
Summary
Legionella pneumophila can cause Legionnaires’ disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). The effector RidL binds the Vps[29] retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. L. pneumophila determines pathogen–host interactions by means of a small signaling molecule[29], and to a large part through a type IV secretion system (T4SS) termed Icm/Dot (intracellular multiplication/defective organelle trafficking)[30]. This T4SS translocates the amazing number of ~ 300 different so-called “effector” proteins into host cells, where they subvert pivotal processes such as signal transduction, protein production and turnover, as well as membrane and cytoskeleton dynamics[31,32,33,34]. Some of the Icm/Dot substrates promote intracellular bacterial replication by targeting host factors such as phytate[35], PI lipids[33,36,37,38,39], small GTPases[31,32,40], or the retromer complex[18]
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