The Legionella Effector RidL Inhibits Retrograde Trafficking to Promote Intracellular Replication

Abstract

The bacteria causing Legionnaires' disease, Legionella pneumophila, replicate intracellularly within unique Legionella-containing vacuoles (LCVs). LCV formation involves a type IV secretion system (T4SS) that translocates effector proteins into host cells. We show that the T4SS effector RidL localizes to LCVs, supports intracellular bacterial growth, and alters retrograde trafficking, in which selected proteins are transported from endosomes to the Golgi. The retromer complex that mediates retrograde trafficking localizes to LCVs independently of RidL and restricts intracellular bacterial growth. RidL binds the Vps29 retromer subunit and the lipid PtdIns(3)P, which localizes retromer components to membranes. Additionally, specific retromer cargo receptors and sorting nexins that mediate protein capture and membrane remodeling preferentially localize to LCVs in the absence of ridL. Ectopic RidL production inhibits retrograde trafficking, and L. pneumophila blocks retrograde transport at endosome exit sites in a ridL-dependent manner. Collectively, these findings suggest that RidL inhibits retromer function to promote intracellular bacterial replication.

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Retromer-related dysfunctions have been reported not only in neurological disorders such as Down syndrome [29,30], hereditary spastic paraplegia [31], cerebral lipofuscinosis [32], prionopathy [33], and Nieman Pick type C1 disease [34], but have also been linked to non-neurological disorders such as type II diabetes [35,36], osteoporosis [37], retinal degeneration [38], and Legionella disease [39] (see Table 1). Several of these diseases have a clear pathological molecular link to retromer; in other cases, the connection is less clear and more tangential.…”

A Type IV Translocated Legionella Cysteine Phytase Counteracts Intracellular Growth Restriction by Phytate

“…Phosphate Release and Protein-Lipid Overlay Assay-GST fusion proteins were purified as described previously (25). Phytate (phytic acid sodium salt hydrate) was obtained from Sigma-Aldrich, and synthetic dioctyl PI and inositol phosphates were purchased from Echelon Biosciences Inc. (Salt Lake City, UT).…”

“…Some L. pneumophila Icm/Dot substrates target and subvert pivotal regulators of eukaryotic signal transduction and vesicle trafficking, such as small GTPases (8 -13) or phosphoinositide (PI) lipids (14 -16). Several Legionella effectors anchor to the LCV membrane by specifically binding to the phosphorylated phosphatidylinositol (PtdIns) headgroup of PI lipids, namely PtdIns(4)P (17)(18)(19)(20)(21)(22) and PtdIns(3)P (23)(24)(25), which are implicated in secretory and endosomal vesicle trafficking, respectively. Moreover, L. pneumophila produces two non-homologous Icm/Dot-translocated PI 3-phosphatases, SidF and SidP, which might modulate the LCV PI pattern (26,27).…”

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

“…Preferences in the PIP-binding specificity might thereby indicate the subcellular compartments to which these effectors are targeted or the stage of infection at which they are associated with the LCV. PI(3)P is preferentially bound by LtpD (Harding et al 2013a), RidL (Finsel et al 2013), SetA (Jank et al 2012), LidA (Brombacher et al 2009), and LpnE ). The effectors SidC, Lem4, Lem28, and SidM/DrrA specifically bind PI(4)P (Ragaz et al 2008;Brombacher et al 2009;Hubber et al 2014).…”

“…The retrograde trafficking pathway delivers material from the plasma membrane and endosomes to the ER via the Golgi apparatus (Johannes and Wunder 2011;Finsel et al 2013). Disruption of retrograde trafficking by RNA interference (RNAi) promotes intracellular replication of Legionella (Finsel et al 2013). To block retrograde trafficking, Legionella translocates the effector RidL (Fig.…”