Intracellular sphingosine releases calcium from lysosomes

Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D.; Platt, Frances M.; Galione, Antony; Schultz, Carsten

doi:10.7554/elife.10616

Cited by 125 publications

(157 citation statements)

References 80 publications

(99 reference statements)

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“…Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome-associated genes (Settembre and Medina, 2015). As lysosomal Sph can activate TFEB (Höglinger et al, 2015), we examined TFEB localization during the clearance of SK1-I-induced vacuoles. Indeed, TFEB translocates to the nucleus prior to vacuole clearance (Figures 7A and 7B).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking

et al. 2016

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“…It has been shown that sphingosine generation within lysosomes also mediates lysosomal permeability and compromises lysosomal integrity [55, 56]. It is certainly possible that S. aureus α-toxin does not only activate the acid sphingomyelinase, but also the acid ceramidase, and thereby triggers the formation of ceramide and sphingosine.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Gulbins

Edwards

et al. 2017

Cell Physiol Biochem

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Background/Aims: Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.

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“…Since ceramides produced in the lysosome by ASM are not shuttled to other subcellular compartments, they may directly influence the coalescence of microdomains required for lysosomal signaling (7). However, ASM forms a molecular complex with acid ceramidase, which metabolizes ceramide to sphingosine, a molecule itself implicated in autophagy via alterations of lysosomal calcium efflux (8). We investigated if ASM is required for LYNUS function of by guest, on www.jlr.org Downloaded from inhibition of autophagy during homeostatic conditions, hypothesizing that inhibition of ASM is sufficient to trigger autophagy associated with disrupted LYNUS signaling.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy

Justice

Bronova

Schweitzer

et al. 2018

Journal of Lipid Research

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Activation of the lysosomal ceramide-producing enzyme, acid sphingomyelinase (ASM), by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on the lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB). ASM inhibition with imipramine or sphingomyelin phosphodiesterase 1 (SMPD1) siRNA in human lung cells, or by transgenic Smpd1+/− haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase (Thr 389)-phosphorylation and modified TFEB in a pattern consistent with its activation. Inhibition of baseline ASM activity significantly increased autophagy with preserved degradative potential. Pulse labeling of sphingolipid metabolites revealed that ASM inhibition markedly decreased sphingosine (Sph) and Sph-1-phosphate (S1P) levels at the level of ceramide hydrolysis. These findings suggest that ASM functions to maintain physiological mTOR signaling and inhibit autophagy and implicate Sph and/or S1P in the control of lysosomal function.

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Intracellular sphingosine releases calcium from lysosomes

Cited by 125 publications

References 80 publications

Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking

Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking

Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy

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