Phosphoinositides differentially regulate bacterial uptake and Nramp1-induced resistance to<i>Legionella</i>infection in<i>Dictyostelium</i>

Peracino, Barbara; Balest, Alessandra; Bozzaro, Salvatore

doi:10.1242/jcs.072124

Cited by 56 publications

(99 citation statements)

References 86 publications

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“…The nramp1 gene (DDB_G0276973) is the ortholog of mammalian nramp1 and was characterized previously (Peracino et al, 2006;Peracino et al, 2010). The nramp2 gene (DDB_G0275815) encodes a putative integral membrane protein with 12 transmembrane domains and a M r of 70 kDa, 10 kDa larger than Nramp1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…How can inactivation of Nramp2, which is localized in the contractile vacuole, have a similar effect, if Nramp1 is active? We have recently shown that Legionella effectively hinders recruitment of the V-H + -ATPase, but not Nramp1, to the Legionella-containing macropinosome (Peracino et al, 2010). In the absence of the vacuolar ATPase, Nramp1 pumping activity is neutralized, and iron may be sequestered by the Legionella (Peracino et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…We showed previously that Nramp1 KO mutants were more susceptible to infection by L. pneumophila and Mycobacterium avium (Peracino et al, 2006;Peracino et al, 2010). This prompted us to test whether disrupting Nramp2 also affected resistance to invasive bacteria and whether the double mutation resulted in any additional effect.…”

Section: Differential Effects Of Iron Depletion or Overload On Mutantmentioning

confidence: 98%

“…Recently, we also showed that L. pneumophila hinders recruitment of the V-H + -ATPase, but not Nramp1, in the Legionella-containing vacuole in a process apparently involving inhibition of phosphatidylinositol-3-phosphate formation. By avoiding colocalization of V-H + -ATPase with Nramp1 in the same vesicle, Legionella neutralizes the proton-driven iron export via Nramp1, and may even turn the protein activity to its advantage (Peracino et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

Peracino

Buracco

Bozzaro

2013

Journal of Cell Science

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SummaryThe Dictyostelium discoideum genome harbors two genes encoding members of the Nramp superfamily, which is conserved from bacteria (MntH proteins) to humans (Slc11 proteins). Nramps are proton-driven metal ion transporters with a preference for iron and manganese. Acquisition of these metal cations is vital for all cells, as they act as redox cofactors and regulate key cellular processes, such as DNA synthesis, electron transport, energy metabolism and oxidative stress. Dictyostelium Nramp1 (Slc11a1), like its mammalian ortholog, mediates resistance to infection by invasive bacteria. We have extended the analysis to the nramp2 gene, by generating single and double nramp1/nramp2 knockout mutants and cells expressing GFP fusion proteins. In contrast to Nramp1, which is recruited to phagosomes and macropinosomes, the Nramp2 protein is localized exclusively in the membrane of the contractile vacuole, a vesicular tubular network regulating cellular osmolarity. Both proteins colocalize with the V-H + -ATPase, which can provide the electrogenic force for vectorial transport. Like nramp1, nramp2 gene disruption affects resistance to Legionella pneumophila. Disrupting both genes additionally leads to defects in development, with strong delay in cell aggregation, formation of large streams and multi-tipped aggregates. Single and double mutants display differential sensitivity to cell growth under conditions of iron overload or depletion. The data favor the hypothesis that Nramp1 and Nramp2, under control of the V-H + -ATPase, synergistically regulate iron homeostasis, with the contractile vacuole possibly acting as a store for metal cations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Differential Effects Of Iron Depletion or Overload On Mutantmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

Peracino

Buracco

Bozzaro

2013

Journal of Cell Science

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“…Confocal series images were taken as described previously (Peracino et al, 2010;Buracco et al, 2015).…”

Section: Fluorescence Microscopy Imagingmentioning

confidence: 99%

A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

Pergolizzi

Bracco

Bozzaro

2017

Journal of Cell Science

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Cyclic AMP (cAMP) binding to G-protein-coupled receptors (GPCRs) orchestrates chemotaxis and development in Dictyostelium. By activating the RasC-TORC2-PKB (PKB is also known as AKT in mammals) module, cAMP regulates cell polarization during chemotaxis. TORC2 also mediates GPCR-dependent stimulation of adenylyl cyclase A (ACA), enhancing cAMP relay and developmental gene expression. Thus, mutants defective in the TORC2 Pia subunit (also known as Rictor in mammals) are impaired in chemotaxis and development. Near-saturation mutagenesis of a Pia mutant by random gene disruption led to selection of two suppressor mutants in which spontaneous chemotaxis and development were restored. PKB phosphorylation and chemotactic cell polarization were rescued, whereas Pia-dependent ACA stimulation was not restored but bypassed, leading to cAMP-dependent developmental gene expression. Knocking out the gene encoding the adenylylcyclase B (ACB) in the parental strain showed ACB to be essential for this process. The gene tagged in the suppressor mutants encodes a newly unidentified HECT ubiquitin ligase that is homologous to mammalian HERC1, but harbours a pleckstrin homology domain. Expression of the isolated wild-type HECT domain, but not a mutant HECT C5185S form, from this protein was sufficient to reconstitute the parental phenotype. The new ubiquitin ligase appears to regulate cell sensitivity to cAMP signalling and TORC2-dependent PKB phosphorylation.

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The life stage‐specific pathometabolism of Legionella pneumophila

Eisenreich

Heuner

2016

FEBS Letters

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The genus Legionella belongs to Gram-negative bacteria found ubiquitously in aquatic habitats, where it grows in natural biofilms and replicates intracellularly in various protozoa (amoebae, ciliates). L. pneumophila is known as the causative agent of Legionnaires' disease, since it is also able to replicate in human alveolar macrophages, finally leading to inflammation of the lung and pneumonia. To withstand the degradation by its host cells, a Legionellacontaining vacuole (LCV) is established for intracellular replication, and numerous effector proteins are secreted into the host cytosol using a type four B secretion system (T4BSS). During intracellular replication, Legionella has a biphasic developmental cycle that alternates between a replicative and a transmissive form. New knowledge about the host-adapted and life stagedependent metabolism of intracellular L. pneumophila revealed a bipartite metabolic network with life stage-specific usages of amino acids (e.g. serine), carbohydrates (e.g. glucose) and glycerol as major substrates. These metabolic features are associated with the differentiation of the intracellular bacteria, and thus have an important impact on the virulence of L. pneumophila.

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Phosphoinositides differentially regulate bacterial uptake and Nramp1-induced resistance toLegionellainfection inDictyostelium

Cited by 56 publications

References 86 publications

The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

The life stage‐specific pathometabolism of Legionella pneumophila

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