Exploitation of Phosphoinositides by the Intracellular Pathogen,<i>Legionella pneumophila</i>

Pike, Colleen M.; Noll, Rebecca R.; Neunuebel, M. Ramona

doi:10.5772/intechopen.89158

Cited by 3 publications

(6 citation statements)

References 108 publications

(145 reference statements)

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“…This led us to speculate that Lpg2411 may interact with a 121 membrane-associated component such as a protein or lipid. 122 Several previously identified effectors recognize membrane compartments by 123 selectively binding phosphoinositide lipids (PIP) (reviewed in (Pike et al, 2019a)).…”

Section: Resultsmentioning

confidence: 99%

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Legionella pneumophila targets autophagosomes and promotes host autophagy during late infection

Noll

Pike

Lehman

et al. 2021

Preprint

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Autophagy is a fundamental eukaryotic process that mediates clearance of unwanted molecules and facilitates nutrient release. The bacterial pathogen Legionella pneumophila establishes an intracellular niche within phagocytes by manipulating host cellular processes, such as autophagy. Effector proteins translocated by L. pneumophila’s Dot/Icm type IV secretion system have been shown to suppress autophagy. However evidence suggests that overall inhibition of autophagy may be detrimental to the bacterium. As autophagy contributes to cellular homeostasis and nutrient acquisition, L. pneumophila may translocate effectors that promote autophagy for these benefits. Here, we show that effector protein Lpg2411 binds phosphatidylinositol-3-phosphate lipids and preferentially binds autophagosomes. Translocated Lpg2411 accumulates late during infection and co-localizes with the autophagy receptor p62 and ubiquitin. Furthermore, autophagy is inhibited to a greater extent in host cells infected with a mutant strain lacking Lpg2411 compared to those infected with wild-type L. pneumophila, indicating that Lpg2411 stimulates autophagy to support the bacterium’s intracellular lifestyle.SummaryLegionella pneumophila translocates several effector proteins that inhibit autophagic processes. In this study, we find that the effector protein Lpg2411 targets autophagosomes during late stages of infection and promotes autophagy.

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Section: Resultsmentioning

confidence: 99%

“…Several previously identified effectors recognize membrane compartments by selectively binding phosphoinositide lipids (PIP) (reviewed in (Pike et al, 2019a)).…”

Section: Resultsmentioning

confidence: 99%

Legionella pneumophila targets autophagosomes and promotes host autophagy during late infection

Noll

Pike

Lehman

et al. 2021

Preprint

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“…Phosphatidylinositol phosphates (PIPs), glycerophospholipids, serve according to their phosphorylation state as important selective membrane receptors and anchors for proteins with PIP-binding domains on the cytosolic leaflet of membranes [137]. Indeed, a large number of Legionella effectors exploit predominantly PI3P- and PI4P-specific lipid-binding domains to associate with membranes and shape PIP metabolism and distribution in the cell () [138, 139] (Effector, ). These PIP-binding and PIP-converting effector domains do not show obvious sequence homology to eukaryotic proteins, suggesting they evolved by convergent evolution [140–142].…”

Section: Dot/icm T4bss Effectorsmentioning

confidence: 99%

The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

et al. 2022

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To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at the host–pathogen interface and/or deliver them directly into host cells. An outstanding example of the complexity and sophistication of secretion systems and the diversity of their protein substrates, effectors, is the Defective in organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB secretion system (T4BSS) of Legionella pneumophila and related species. Legionella species are facultative intracellular pathogens of environmental protozoa and opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number of effectors, more than 300 per L. pneumophila strain, and is essential for evasion of phagolysosomal degradation and exploitation of protozoa and human macrophages as replicative niches. Recent technological advancements in the imaging of large protein complexes have provided new insight into the architecture of the T4BSS and allowed us to propose models for the transport mechanism. At the same time, significant progress has been made in assigning functions to about a third of L. pneumophila effectors, discovering unprecedented new enzymatic activities and concepts of host subversion. In this review, we describe the current knowledge of the workings of the Dot/Icm T4BSS machinery and provide an overview of the activities and functions of the to-date characterized effectors in the interaction of L. pneumophila with host cells.

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“…This programmed conversion of PIs 4 on the LCV is mediated by a number of PI kinases (24)(25)(26)(27) and phosphatases (28)(29)(30), as well as phospholipases (31)(32)(33), from both the bacterium and the host. The spatiotemporal control of PI composition on the LCV provides a dynamic anchoring platform for a large number of Legionella effectors harboring unique domains that specifically bind to PI(4)P and/or PI(3)P (18,34).…”

Section: Introductionmentioning

confidence: 99%

“…These PI-binding domains adopt a variety of structural folds and apply diverse strategies for PI recognition and membrane association (9,10). PI-binding domains are not restricted to proteins from eukaryotes; new PIbinding modules have frequently been discovered in bacterial pathogens (11)(12)(13)(14), particularly in the opportunistic pathogen Legionella pneumophila (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Solution structure of the phosphatidylinositol 3-phosphate binding domain from theLegionellaeffector SetA

Beck

Enoki

et al. 2022

Preprint

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Legionella pneumophila is a facultative intracellular pathogen that causes Legionnaires' disease or Pontiac fever in humans upon accidental inhalation of Legionella-contaminated aerosols. During infection, L. pneumophila secretes more than 300 effectors into the host for the biogenesis of a replication-permissive niche, known as the Legionella containing vacuole (LCV). Among these, a large number of effectors harbor protein domains that recognize specific phosphoinositide (PI) lipids and mediate the anchoring of these effectors to the surface of LCV or other host membrane-bound organelles. The Legionella effector SetA contains a unique C-terminal domain (SetA-CTD) that has been shown to specifically bind with phosphatidylinositol-3-phosphate (PI(3)P) and target SetA to endosomes and LCVs. Here, we report the NMR solution structure of SetA-CTD, which mainly comprises a four alpha-helix bundle. The structure reveals a basic pocket at one end of the alpha-helix bundle for PI(3)P binding and two hydrophobic loops for membrane insertion. Mutations of key residues involved in lipid binding result in the loss of SetA in membrane association and endosomal localization. Structural comparison with other PI(3)P-binding domains highlights a general theme applied by multiple families of phosphoinositide-binding domains across species.

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Exploitation of Phosphoinositides by the Intracellular Pathogen,Legionella pneumophila

Cited by 3 publications

References 108 publications

Legionella pneumophila targets autophagosomes and promotes host autophagy during late infection

Legionella pneumophila targets autophagosomes and promotes host autophagy during late infection

The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

Solution structure of the phosphatidylinositol 3-phosphate binding domain from theLegionellaeffector SetA

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