Abstract
Genetic studies have suggested a functional link between cholesterol/sphingolipid metabolism and endocytic membrane traffic. Here we show that perturbing the cholesterol/sphingomyelin balance in the plasma membrane results in the massive formation of clusters of narrow endocytic tubular invaginations positive for N-BAR proteins. These tubules are intensely positive for sphingosine kinase 1 (SPHK1). SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals, which are cellular compartments specialized for exo/endocytosis. Membrane recruitment of SPHK1 involves a direct, curvature-sensitive interaction with the lipid bilayer mediated by a hydrophobic patch on the enzyme’s surface. The knockdown of SPHKs results in endocytic recycling defects, and a mutation that disrupts the hydrophobic patch of Caenorhabditis elegans SPHK fails to rescue the neurotransmission defects in loss-of-function mutants of this enzyme. Our studies support a role for sphingosine phosphorylation in endocytic membrane trafficking beyond the established function of sphingosine-1-phosphate in intercellular signalling.
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Acknowledgements
We thank L. Liang and J. Duncan (Yale University) for help with the automatic tracking of clathrin-coated pits dynamics, S. Ferguson, A. Frost and T. Walther for discussion and advice, J. Baskin for thorough reading of the manuscript, F. Wilson, L. Lucast, L. Liu and H. Czapla for outstanding technical support, M. Graham, X. Liu and S. Wilson for help with microscopy experiments, and members of T. Walther, T. Melia and C. Burd laboratories (Yale University) for help with lipid experiments. We also acknowledge the help of the Yale Center for Cellular and Molecular Imaging and Yale Center for Genomics and Proteomics. This work was supported in part by grants from the NIH (NS36251, DK45735 and DA018343 to P.D.C., GM097552 to T.B., and NS071085 to D.S.) and from the Ellison Medical Foundation to P.D.C.
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H.S. and P.D.C. designed the experiments and wrote the manuscript; H.S. performed the experiments. Experimental work was also contributed by F.G. (electron microscopy), Y.W. (electron microscopy), J.C. and D.S. (C. elegans experiments), C.Z. (curvature sorting), I.M. (neuronal experiment), K.Y. (retina experiment) and X.W. (circular dichroism spectroscopy).
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Supplementary Figure 1 Acute perturbation of plasma membrane cholesterol induces massive endocytic tubular invaginations positive N-BAR proteins.
a. Confocal image of a cell expressing GFP-tagged endophilin 2ΔSH3 after MβCD treatment. b,c. Formation of endophilin 2 foci in different cell lines on MβCD treatment. MEF =mouse embryonic fibroblast. For each cell type, 50 cells expressing endophilin-2–GFP were counted and percentages of the cells that contain endophilin 2 clusters were plotted. Data represent a single experiment. d. Anti-endophilin 2 immunofluorescence staining of a control cell or a cell treated with MβCD for 5 min (+MβCD). e. Cell co-expressing amphiphysin 2-GFP and endophilin-2–Ruby after MβCD treatment. f. Confocal image of an endophilin TKO cell expressing amphiphysin 2-GFP before and after MβCD treatment. g. Confocal images of a WT cell expressing endophilin-2–Ruby (left), after MβCD treatment (middle) and supplemented with cholesterol after MβCD treatment (right). h. Confocal image of a cell expressing endophilin-2–GFP treated with HPβCD (an analogue of MβCD). Scale bar, 10 mμ in a,b,d,f and h; 5 μm in e and g.
Supplementary Figure 2 Characterization of endocytic tubular invaginations induced by perturbation of plasma membrane cholesterol.
a, b. Double fluorescence images showing that endophilin 2 foci are positive for chemical (TopFluor-PS, a and genetically encoded (C2lact-GFP, b PtdSer markers. c,d. Double fluorescence images showing that endophilin 2 foci are negative for the genetically encoded PI(4,5)P2 probe (GFP-PHPLC, c and immunoreactivity recognized by an anti-PI(4,5)P2 antibody, d,e. Double fluorescence images showing that endophilin 2 foci are negative for the genetically encoded PI3P probe GFP-FYVEHrs. f, Scanning electron microscopy micrographs of a mouse fibroblast before (left) and after (right) MβCD treatment. Framed regions, which are shown at a higher magnification at the right of each field, highlight the disappearance of filopodia after treatment. g, Representative example of the change in the footprint of a cell labeled by PM-GFP before (white) and after MβCD treatment (gray). h,i, Representative images (h) and quantification (i) of endophilin 2 foci induced by MβCD in WT, clathrin heavy chain (CHC) knockdown (KD), and dynamin triple KO mouse fibroblasts. n = 37 (WT), 36 (CHC KD), and 38 (dyn TKO). Pooled data from three independent experiments. Error bars represent standard errors of the mean. [ns] not significant; [***] P < 0.001, Student’s t-test. j, Double fluorescence confocal images of a cell expressing dynamin 2-RFP and endophilin-2–GFP after MβCD treatment. k, Double fluorescence confocal images of a cell expressing dynamin 2-RFP and endophilin-2ΔSH3–GFP after MβCD treatment. Scale bar, 3 μm in a–e,j and k and 10 βm in f,g and h, All pictures shown in the figure are from mouse fibroblasts.
Supplementary Figure 3 The sphingoid base modifying enzyme, sphingosine kinase 1 (SPHK1), is recruited to the endophilin 2 foci.
a. A genetic interaction map in budding yeast30 revealed a genetic interaction between RVS161 and RVS167 and genes encoding enzymes involved in sphingolipid and ergosterol synthesis (top). Blue and yellow indicate negative and positive interaction, respectively. The interactions of RVS161 and RVS167 with enzymes regulating sphingoid base level are framed by a purple rectangle. The corresponding pathway and orthologous mammalian enzymes (black letters) are shown at the bottom. b, Localization of several sphingolipid metabolic enzymes (all transmembrane proteins with the exception of CerK) in mammalian cells as shown by confocal microscopy analysis of transfected GFP-fusion proteins. SMPD3: neutral sphingomyelinase 2 (plasma membrane); ASAH2: neutral ceramidase 2 (plasma membrane); CerK: ceramide kinase (plasma membrane, but also partially cytosolic); SGPP1: sphingosine-1-phosphate phosphatase 1 (ER); CerS1: ceramide synthase 1 (ER); SGPL1: sphingosine-1-phosphate lyase 1 (ER). c, Sphingolipid metabolic pathway where the enzymes analysed in b is shown in red. d, Double fluorescence images of a cell expressing endophilin-2–GFP and SPHK2-FLAG following MβCD treatment, fixation and subsequent immunostaining with anti-FLAG antibody. e, Confocal image of an endophilin triple KO cell expressing SPHK1-GFP after MβCD treatment. Scale bar, 10 μm in b and e; and 5 μm in d.
Supplementary Figure 4 SPHK1 and SPHK2 knockdown in HeLa cells.
HeLa cells were transfected with control siRNA (ctrl) or siRNA directed against SPHK1 and SPHK2 (DKD). SPHK1 and SPHK2 mRNA levels were measured by real-time qPCR. n = 3 measurements. Error bar: standard error of the mean. Data are from one experiment, but are representative of three independent experiments.
Supplementary Figure 5 In vitro assay of purified SPHK1.
a. Coomassie-stained SDS-PAGE showing purified SPHK1-GFP-FLAG. b, Sphingosine kinase assay. Autoradiography of a TLC plate showing that purified SPHK1 is catalytically active as it phosphorylates sphingosine to generate radiolabeled sphingosine-1-phosphate in vitro. As the two lanes shown in the image were from the same TLC plate but not adjacent to each other, a black splice mark was included to separate the two lanes. The full TLC plate from which the data are extracted is shown in Supplementary Fig. 7c. The presence of SPHK1 on the membrane bilayer does not change the relationship between tubule radius and tension in the membrane tethering assay. n = 6 (with SPHK1) and 9 (without SPHK) pulled tubules. Each tubule represents an independent experiment, and data from independent experiments are averaged. Error bars represent standard error of the mean.
Supplementary Figure 6 Human SPHK1 rescues the synaptic transmission defect observed in SPHK-1 mutant worms.
Time-course of the onset of paralysis of the indicated worm strains on exposure to the acetylcholine esterase inhibitor aldicarb (1 mM). sphk-1; H.s. SPHK1 stands for sphk-1 null mutants expressing full length human SPHK1 cDNA in neurons. n = 3 plates. One transgenic line was assayed and 25 animals were examined from each plate. Average paralysis rate was determined by pooling data from the three assays. Error bars represent standard error of the mean.
Supplementary Figure 7 Original TLC from which the data of Supplementary Fig. 5b were extracted (lanes 2 and 7).
Lane 3–6 are from a purified SPHK1 expressed in bacteria.The low catalytic activity of this preparation most likely reflects protein misfolding. For this reason, SPHK1 was expressed in and purified from mammalian cells, Expi293F cells (lanes 1 and 2). Lane 7 is the control where no protein was added in the reaction.
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Spinning disk confocal movie of HeLa cells expressing endophilin-2–GFP on MβCD treatment.
Spinning disc confocal microscopy of HeLa cells expressing endophilin-2–GFP showing the formation and disappearance of the large endophilin foci during 10 mM MβCD treatment. The interval between frames is 4 s. Playback rate is 12 frames per second. Scale bar, 10 μm. (AVI 2073 kb)
Transmission electron microscopy tomography of a tubular membrane cluster generated by MβCD treatment.
Mouse fibroblasts expressing endophilin-2–GFP were treated with 10 mM MβCD, and processed as described in the Methods section. A plastic section (250 nm) containing a tubular cluster was visualized by electron tomography. (MOV 8991 kb)
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Shen, H., Giordano, F., Wu, Y. et al. Coupling between endocytosis and sphingosine kinase 1 recruitment. Nat Cell Biol 16, 652–662 (2014). https://doi.org/10.1038/ncb2987
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DOI: https://doi.org/10.1038/ncb2987
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