Identification and Structural Characterization of a Legionella Phosphoinositide Phosphatase*

Toulabi, Leila; Wu, Xiaochun; Cheng, Yanshu; Mao, Yuxin

doi:10.1074/jbc.m113.474239

Cited by 72 publications

(76 citation statements)

References 60 publications

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“…Intravacuolar pathogens subvert PI metabolism to manipulate the lipid profile of their host-derived replicative niche, thus controlling the interactions with the endosomal maturation pathway according to their needs. Mycobacterium tuberculosis (35,36) and Legionella pneumophila (37,38) use effectors to deplete PI(3)P at the surface of their vacuoles to block phagosomal maturation and avoid fusion with degradative compartments. On the contrary, Salmonella enterica serovar Typhimurium uses the SPI-1 substrate SopB to maintain elevated levels of PI(3)P at the surface of Salmonella-containing vacuoles, favoring their biogenesis (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Martínez

Allombert

Cantet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

129

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The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome-and autophagy-derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella-containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations.Coxiella burnetii | host-pathogen interactions | phosphoinositides

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Section: Discussionmentioning

confidence: 99%

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Martínez

Allombert

Cantet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

129

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“…After engulfment by phagocytes, L. pneumophila uses its Dot/Icm type IV secretion system to deliver a large number of effector proteins that modulate host cellular processes, leading to the creation of a specialized Legionella-containing vacuole (LCV) that provides the environment for robust intracellular bacterial growth (2). The mature LCV is characterized by an enrichment of a particular phosphoinositide lipid, PI(4)P (3)(4)(5), and by the accumulation of endoplasmic reticulum (ER) proteins, presumably captured by intercepting vesicles derived from the ER (6,7). Another feature of the LCV is enrichment of polyubiquitin conjugates around the vacuolar membrane (8).…”

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confidence: 99%

The Legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling

Hsu

Luo

Qiu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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110

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The activity of proteins delivered into host cells by the Dot/Icm injection apparatus allows Legionella pneumophila to establish a niche called the Legionella-containing vacuole (LCV), which is permissive for intracellular bacterial propagation. Among these proteins, substrate of Icm/Dot transporter (SidC) anchors to the cytoplasmic surface of the LCV and is important for the recruitment of host endoplasmic reticulum (ER) proteins to this organelle. However, the biochemical function underlying this activity is unknown. Here, we determined the structure of the N-terminal domain of SidC, which has no structural homology to any protein.Sequence homology analysis revealed a potential canonical catalytic triad formed by Cys46, His444, and Asp446 on the surface of SidC. Unexpectedly, we found that SidC is an E3 ubiquitin ligase that uses the C-H-D triad to catalyze the formation of highmolecular-weight polyubiquitin chains through multiple ubiquitin lysine residues. A C46A mutation completely abolished the E3 ligase activity and the ability of the protein to recruit host ER proteins as well as polyubiquitin conjugates to the LCV. Thus, SidC represents a unique E3 ubiquitin ligase family important for phagosomal membrane remodeling by L. pneumophila.

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“…The conserved amino acid motif CX 5 R is a hallmark of the "P-loop" (phosphate-binding) catalytic site of the prototypic cysteine phytase PhyA in Selenomonas ruminantium (39) as well as of eukaryotic and prokaryotic PI phosphatases, such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), L. pneumophila SidF and SidP (26,27,40), dual specificity Ser/Thr and Tyr protein phosphatases (DSP) (41), and the triple specificity DSP/PI phosphatase MptpB from Mycobacterium tuberculosis (42,43).…”

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confidence: 99%

“…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). SidF localizes to the LCV membrane and hydrolyzes in vitro the phagosomal/endosomal PIs PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 , possibly yielding PtdIns(4)P on LCVs directly or through the activity of the host PI 5-phosphatase OCRL1 (23).…”

mentioning

confidence: 99%

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

Weber

Stirnimann

Wieser

et al. 2014

Journal of Biological Chemistry

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Background: Legionella governs pathogen-host interactions by translocating ϳ300 "effector" proteins through a type IV secretion system. Results: The hitherto unrecognized effector LppA is a phytase that counteracts intracellular bacterial growth restriction by phytate. Conclusion:The chelator phytate is a bacteriostatic component of cell-autonomous immunity, which is degraded by a bacterial effector. Significance: Legionella LppA represents the first translocated phytase and a potential therapeutic target.

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Identification and Structural Characterization of a Legionella Phosphoinositide Phosphatase*

Cited by 72 publications

References 60 publications

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

The Legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling

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

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