Loss of Dictyostelium ATG9 results in a pleiotropic phenotype affecting growth, development, phagocytosis and clearance and replication of Legionella pneumophila

Tung, Sze Man; Ünal, Can; Ley, Alexandra C.; Peña, Cohue; Tunggal, Budi; Noegel, Angelika A.; Krut, Oleg; Steinert, Michael; Eichinger, Ludwig M.

doi:10.1111/j.1462-5822.2010.01432.x

Cited by 86 publications

(135 citation statements)

References 53 publications

(122 reference statements)

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“…inactivation, at least for the genes examined thus far; 78,79,83,84 a result which mirrors the phenotypes seen in parasitic protists where autophagy is also important during cellular differentiation-see next main section.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 54%

“…81,82 Phenotypic analysis of the various ATG gene knock-outs that have been made in D. discoideum reveals that the absence of various ATG components either compromises or results in failure of fruiting body formation, but that failure of the developmental program occurs at different points depending upon the ATG gene that is inactivated. 78,79,83,84 Following ATG gene inactivation, the morphological defect that occurs during development can vary depending upon the experimental protocol used to induce multicellular development. Thus, amoebae can be grown axenically and then starved on nitrocellulose filters, induced for development within plaques on bacterial lawns or grown on bacterial lawns and then transferred to nitrocellulose for starvation-induced development.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

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Autophagy in protists

et al. 2011

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Autophagy is the degradative process by which eukaryotic cells digest their own components using acid hydrolases within the lysosome. Originally thought to function almost exclusively in providing starving cells with nutrients taken from their own cellular constituents, autophagy is in fact involved in numerous cellular events including differentiation, turnover of macromolecules and organelles, and defense against parasitic invaders. During the last 10-20 years, molecular components of the autophagic machinery have been discovered, revealing a complex interactome of proteins and lipids, which, in a concerted way, induce membrane formation to engulf cellular material and target it for lysosomal degradation. Here, our emphasis is autophagy in protists. We discuss experimental and genomic data indicating that the canonical autophagy machinery characterized in animals and fungi appeared prior to the radiation of major eukaryotic lineages. Moreover, we describe how comparative bioinformatics revealed that this canonical machinery has been subject to moderation, outright loss or elaboration on multiple occasions in protist lineages, most probably as a consequence of diverse lifestyle adaptations. We also review experimental studies illustrating how several pathogenic protists either utilize autophagy mechanisms or manipulate host-cell autophagy in order to establish or maintain infection within a host. The essentiality of autophagy for the pathogenicity of many parasites, and the unique features of some of the autophagy-related proteins involved, suggest possible new targets for drug discovery. Further studies of the molecular details of autophagy in protists will undoubtedly enhance our understanding of the diversity and complexity of this cellular phenomenon and the opportunities it offers as a drug target

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Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 54%

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Autophagy in protists

et al. 2011

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“…L. pneumophila replicated better when the autophagy machinery was impaired by disrupting ATG9 in D. discoideum (SI Appendix, Fig. S9A) (24,50). Similarly, mSPL also contributes to restriction of L. pneumophila growth, as deletion of the gene encoding mSPL enhances intracellular replication of L. pneumophila (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Rolando

Escoll

Nora

et al. 2016

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

115

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Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, an intracellular pathogen that can cause a severe pneumonia in humans, is able to modulate autophagy through the action of effector proteins that are translocated into the host cell by the pathogen's Dot/Icm type IV secretion system. Many of these effectors share structural and sequence similarity with eukaryotic proteins. Indeed, phylogenetic analyses have indicated their acquisition by horizontal gene transfer from a eukaryotic host. Here we report that L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl was required for efficient infection of A/J mice, highlighting an important virulence role for this effector. Thus, we have uncovered a previously unidentified mechanism used by intracellular pathogens to inhibit autophagy, namely the disruption of host sphingolipid biosynthesis.Legionella pneumophila | sphingosine-1-phosphate lyase | autophagy | sphingolipids | virulence T he Gram-negative intracellular bacterium Legionella pneumophila is an opportunistic human pathogen responsible for Legionnaires' disease. The bacteria are naturally found in freshwater systems where they replicate within protozoan hosts (1). It is thought that the adaptation to replication within amoebas has equipped L. pneumophila with the factors required to replicate successfully within human macrophages following opportunistic infection (2). Through genome sequencing, we have discovered that L. pneumophila encodes a high number and variety of proteins similar in sequence to eukaryotic proteins that are never or rarely found in other prokaryotic genomes (3). Subsequent phylogenetic analyses have suggested that many of these proteins were acquired by horizontal gene transfer (3, 4). One of these proteins exhibits a high degree of similarity to eukaryotic sphingosine-1 phosphate lyase (SPL). The L. pneumophila SPL homolog (LpSpl encoded by gene lpp2128, lpg2176, or legS2) is conserved in all L. pneumophila strains sequenced to date, but absent from Legionella longbeachae (SI Appendix, Table S1). Phylogenetic analysis of SPL sequences showed that the L. pneumophila spl gene was most likely acquired early during evolution by horizontal gene transfer from a protozoan organism (4, 5). With the increase in genome sequences available...

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“…85 Thus, a strong association between defective autophagy and impaired properties counteracting bacterial infections has been reported by numerous studies. 73,[86][87][88][89] However, a recent study has revealed a protective role of Atg16l1 deficiency against intestinal disease induced by the bacterial pathogen model, Citrobacter rodentium. This immunosuppressive role of ATG16L1 deficiency is dependent on the presence of NOD2 90 and adds to the complexity of the role of ATG16L1 in bacterial clearance.…”

Section: Atg16l1-dependent Signaling In Crohn Diseasementioning

confidence: 99%