Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

Moruno-Manchon, Jose F.; Uzor, Ndidi-Ese; Dabaghian, Yu.; Furr-Stimming, Erin; Finkbeiner, Steven; Tsvetkov, Andrey S.

doi:10.1038/srep15213

Cited by 78 publications

(112 citation statements)

References 51 publications

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“…S5D). This result is in line with a recent report that suggests that S1P is an initiator of autophagosome formation and SPL an inhibitor of autophagy in primary cells (45). Thus, ectopic expression of LpSpl can prevent autophagosome formation under nutrient limiting conditions.…”

Section: Resultssupporting

confidence: 92%

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

Rolando

Escoll

Nora

et al. 2016

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

119

130

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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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Section: Resultssupporting

confidence: 92%

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

Rolando

Escoll

Nora

et al. 2016

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

119

130

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“…In contrast, in neurons SGPL1 deficiency causes accumulation of S1P on the one hand and a drop in phosphatidylethanolamine on the other hand. The latter proved to block neuronal autophagy flux via an mTOR independent mechanism (Mitroi et al, ), whereas the former was shown to stimulate neuronal autophagy (Moruno Manchon et al, )…”

Section: Discussionmentioning

confidence: 99%

“…Although the modulation of autophagy by sphingolipids has been known for quite a while (Lavieu et al, ; Lepine et al, ), the number of studies that investigated this interrelationship in the brain wherein autophagy is indispensable to recycle aggregate prone proteins is rather scant (Moruno Manchon et al, ; van Echten‐Deckert & Alam, ). We have shown that neurons lacking SGPL1, the enzyme that catalyzes the irreversible cleavage of S1P into hexadecenal and ethanolamine phosphate accumulate S1P that exhibits a neurotoxic effect similar to that of Aβ.…”

Section: Introductionmentioning

confidence: 99%

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Indulekha

Alam

Surendar

et al. 2019

Glia

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Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1‐phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P‐lyase (SGPL1) ablated mice (SGPL1fl/fl/Nes) as shown by an activated and deramified morphology and increased activation markers on microglia. In addition, an increase of pro‐inflammatory cytokines in sorted and primary cultured microglia generated from SGPL1 deficient mice was noticed. Further, we assessed autophagy, one of the major mechanisms in the brain that keeps inflammation in check. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by treatment with rapamycin was sufficient to decrease interleukin 6 (IL‐6) but not tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated decrease of IL‐6 secretion suggests a particular mechanistic target of rapamycin (mTOR)‐IL‐6 link and appeared to be microglia specific. Using pharmacological inhibitors of the major receptors of S1P expressed in the microglia, we identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and proinflammatory effects. In line with these results, the addition of exogenous S1P to BV2 microglial cells showed similar effects as those observed in the genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role of the S1P‐S1PR2 axis in the microglia of mice with neural‐targeted SGPL1 ablation and in BV2 microglial cell line exogenously treated with S1P.

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“…Intriguingly, mTOR associates with sphingolipid-enriched vacuoles to that sphingolipids may regulate mTOR localization (Figure S6). Moreover, sphingolipids are established regulators of autophagy (Young et al, 2013), and the recruitment of SphK1 to endosomes, autophagosomes, and amphisomes has recently been linked to autophagosome biogenesis and degradation (Moruno Manchon et al, 2015; Manchon et al, 2016). Additionally, ceramide directly interacts with LC3-II to mediate cargo recruitment to autophagosomes for efficient degradation (Sentelle et al, 2012; Dany et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking

et al. 2016

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Summary SphK1 associates with early endocytic membranes during endocytosis; however, the role of sphingosine or sphingosine-1-phosphate as the critical metabolite in endocytic trafficking has not been established. Here, we demonstrate that the recruitment of SphK1 to sphingosine-enriched endocytic vesicles and the generation of sphingosine-1-phosphate facilitate membrane trafficking along the endosomal pathway. Exogenous sphingosine and sphingosine-based SphK1 inhibitors induce the SphK1-dependent fusion of endosomal membranes to accumulate enlarged late endosomes and amphisomes enriched in sphingolipids. Interestingly, SphK1 also appears to facilitate endosomal fusion independent of its catalytic activity, as catalytically inactive SphK1G82D is recruited to endocytic membranes by sphingosine or sphingosine-based SphK1 inhibitor and promotes membrane fusion. Furthermore, we reveal that the clearance of enlarged endosomes is dependent on the activity of ceramide synthase, lysosomal biogenesis and the restoration of autophagic flux. Collectively, these studies uncover intersecting roles for SphK1, sphingosine and autophagic machinery in endocytic membrane trafficking.

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Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

Cited by 78 publications

References 51 publications

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

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

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking

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