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Science China Life Sciences

, Volume 62, Issue 9, pp 1117–1135 | Cite as

Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI(4,5)P2 and extended synaptotagmins

  • Jian Xiao
  • Jie Luo
  • Ao Hu
  • Ting Xiao
  • Meixin Li
  • Zekai Kong
  • Luyi Jiang
  • Zimu Zhou
  • Yacheng Liao
  • Chang Xie
  • Beibei Chu
  • Honghua Miao
  • Boliang Li
  • Xiongjie Shi
  • Bao-Liang SongEmail author
Cover Article SCLS-CBIS Joint Life Science Research Workshop

Abstract

Most mammalian cells take up cholesterol from low-density lipoproteins (LDLs) via receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs. Peroxisomes are recently found to receive cholesterol from lysosomes through lysosome-peroxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes, we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1, 2 and 3 (E-Syts). Depletion of peroxisomal PI(4,5)P2 or E-Syts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore, we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro, and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER. Together, our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.

Peroxisome ER membrane contacts E-Syts PI(4, 5)P2 

Notes

Acknowledgements

We thank Dr. Wei Qi for helpful discussion and critical reading of the manuscript. We thank the center for Biological Imaging, Institute of Biophysics, Chinese Academy of Science for 3D TEM experiments, and Xin-Tong Niu and Yun Feng for their help with 3D TEM images. We thank Dr. Ming-Liang Tang for his help with SR-SIM images. This work was supported by the National Natural Science Foundation of China (91754102, 31771568, 31690102, 31600651 and 31701030), National Key Research and Development Project of the Ministry of Science and Technology of China (2016YFA0500100), Shenzhen City Technology Basic Research Program (JCYJ20170818144026198), Science and Technology Department of Hubei Province (2017CFB617) and the 111 Project of Ministry of Education of China (B16036).

Compliance and ethics The authors declare that they have no conflict of interests.

Supplementary material

11427_2019_9569_MOESM1_ESM.pdf (1.8 mb)
Supporting Information
11427_2019_9569_MOESM2_ESM.mp4 (6.4 mb)
Supplementary material, approximately 6.39 MB.

References

  1. Angermuller, S., and Fahimi, H.D. (1981). Selective cytochemical localization of peroxidase, cytochrome oxidase and catalase in rat liver with 3,3′-diaminobenzidine. Histochemistry 71, 33–44.CrossRefGoogle Scholar
  2. Braverman, N.E., and Moser, A.B. (2012). Functions of plasmalogen lipids in health and disease. BBA-Mol Basis Dis 1822, 1442–1452.CrossRefGoogle Scholar
  3. Brose, N., Petrenko, A.G., Sudhof, T.C., and Jahn, R. (1992). Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256, 1021–1025.CrossRefGoogle Scholar
  4. Brown, M.S., and Goldstein, J.L. (1986). A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47.CrossRefGoogle Scholar
  5. Brown, M.S., and Goldstein, J.L. (1997). The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340.CrossRefGoogle Scholar
  6. Cao, J., Wang, J., Qi, W., Miao, H.H., Wang, J., Ge, L., DeBose-Boyd, R. A., Tang, J.J., Li, B.L., and Song, B.L. (2007). Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab 6, 115–128.CrossRefGoogle Scholar
  7. Chang, T.Y., Chang, and, C.C.Y., and Cheng, D. (1997). Acyl-coenzyme A: cholesterol acyltransferase. Annu Rev Biochem 66, 613–638.CrossRefGoogle Scholar
  8. Chang, T.Y., Chang, C.C.Y., Ohgami, N., and Yamauchi, Y. (2006). Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol 22, 129–157.CrossRefGoogle Scholar
  9. Chu, B.B., Liao, Y.C., Qi, W., Xie, C., Du, X., Wang, J., Yang, H., Miao, H. H., Li, B.L., and Song, B.L. (2015). Cholesterol transport through lysosome-peroxisome membrane contacts. Cell 161, 291–306.CrossRefGoogle Scholar
  10. Costello, J.L., Castro, I.G., Hacker, C., Schrader, T.A., Metz, J., Zeuschner, D., Azadi, A.S., Godinho, L.F., Costina, V., Findeisen, P., et al. (2017a). ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. J Cell Biol 216, 331–342.CrossRefGoogle Scholar
  11. Costello, J.L., Castro, I.G., Schrader, T.A., Islinger, M., and Schrader, M. (2017b). Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations. Cell Cycle 16, 1039–1045.CrossRefGoogle Scholar
  12. Das, A., Brown, M.S., Anderson, D.D., Goldstein, J.L., and Radhakrishnan, A. (2014). Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. eLife 3, e02882.CrossRefGoogle Scholar
  13. Demmerle, J., Innocent, C., North, A.J., Ball, G., Müller, M., Miron, E., Matsuda, A., Dobbie, I.M., Markaki, Y., and Schermelleh, L. (2017). Strategic and practical guidelines for successful structured illumination microscopy. Nat Protoc 12, 988–1010.CrossRefGoogle Scholar
  14. Dong, J., Du, X., Wang, H., Wang, J., Lu, C., Chen, X., Zhu, Z., Luo, Z., Yu, L., Brown, A.J., Yang, H., and Wu, J. (2019). Allosteric enhancement of ORP1-mediated cholesterol transport by PI(4,5)P2/PI(3,4)P2. Nat Commun 10, 829.CrossRefGoogle Scholar
  15. Eisenberg-Bord, M., Shai, N., Schuldiner, M., and Bohnert, M. (2016). A tether is a tether is a tether: tethering at membrane contact sites. Dev Cell 39, 395–409.CrossRefGoogle Scholar
  16. Fahimi, H.D., Baumgart, E., and Völkl, A. (1993). Ultrastructural aspects of the biogenesis of peroxisomes in rat liver. Biochimie 75, 201–208.CrossRefGoogle Scholar
  17. Gatta, A.T., and Levine, T.P. (2017). Piecing together the patchwork of contact sites. Trends Cell Biol 27, 214–229.CrossRefGoogle Scholar
  18. Gill, S., Stevenson J, Fau - Kristiana, I., Kristiana I, Fau - Brown, A.J., and Brown, A.J. (2011). Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reducta. Cell Metab 13, 260–273.CrossRefGoogle Scholar
  19. Giordano, F., Saheki, Y., Idevall-Hagren, O., Colombo, S.F., Pirruccello, M., Milosevic, I., Gracheva, E.O., Bagriantsev, S.N., Borgese, N., and De Camilli, P. (2013). PI(4,5)P2-dependent and Ca2+-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153, 1494–1509.CrossRefGoogle Scholar
  20. Goldstein, J.L., DeBose-Boyd, R.A., and Brown, M.S. (2006). Protein sensors for membrane sterols. Cell 124, 35–46.CrossRefGoogle Scholar
  21. Gould, S.J., Keller, G.A., Hosken, N., Wilkinson, J., and Subramani, S. (1989). A conserved tripeptide sorts proteins to peroxisomes. J Cell Biol 108, 1657–1664.CrossRefGoogle Scholar
  22. Gronemeyer, T., Wiese, S., Grinhagens, S., Schollenberger, L., Satyagraha, A., Huber, L.A., Meyer, H.E., Warscheid, B., and Just, W.W. (2013). Localization of Rab proteins to peroxisomes: A proteomics and immunofluorescence study. FEBS Lett 587, 328–338.CrossRefGoogle Scholar
  23. Hu, A., Zhao, X.T., Tu, H., Xiao, T., Fu, T., Wang, Y., Liu, Y., Shi, X.J., Luo, J., and Song, B.L. (2018). PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis. J Lipid Res 59, 507–514.CrossRefGoogle Scholar
  24. Hua, R., Cheng, D., Coyaud, É., Freeman, S., Di Pietro, E., Wang, Y., Vissa, A., Yip, C.M., Fairn, G.D., Braverman, N., et al. (2017). VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis. J Cell Biol 216, 367–377.CrossRefGoogle Scholar
  25. Idevall-Hagren, O., Lü, A., Xie, B., and De Camilli, P. (2015). Triggered Ca2+ influx is required for extended synaptotagmin 1-induced ER-plasma membrane tethering. EMBO J 34, 2291–2305.CrossRefGoogle Scholar
  26. Jeynov, B., Lay, D., Schmidt, F., Tahirovic, S., and Just, W.W. (2006). Phosphoinositide synthesis and degradation in isolated rat liver peroxisomes. FEBS Lett 580, 5917–5924.CrossRefGoogle Scholar
  27. Jiang, L.Y., Jiang, W., Tian, N., Xiong, Y.N., Liu, J., Wei, J., Wu, K.Y., Luo, J., Shi, X.J., and Song, B.L. (2018). Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. J Biol Chem 293, 4047–4055.CrossRefGoogle Scholar
  28. Jin, Y., Strunk, B.S., and Weisman, L.S. (2015). Close encounters of the lysosome-peroxisome kind. Cell 161, 197–198.CrossRefGoogle Scholar
  29. Jungmichel, S., Sylvestersen, K.B., Choudhary, C., Nguyen, S., Mann, M., and Nielsen, M.L. (2014). Specificity and commonality of the phosphoinositide-binding proteome analyzed by quantitative mass spectrometry. Cell Rep 6, 578–591.CrossRefGoogle Scholar
  30. Knoblach, B., Sun, X., Coquelle, N., Fagarasanu, A., Poirier, R.L., and Rachubinski, R.A. (2013). An ER-peroxisome tether exerts peroxisome population control in yeast. EMBO J 32, 2439–2453.CrossRefGoogle Scholar
  31. Kobayashi, T., Beuchat, M.H., Lindsay, M., Frias, S., Palmiter, R.D., Sakuraba, H., Parton, R.G., and Gruenberg, J. (1999). Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol 1, 113–118.CrossRefGoogle Scholar
  32. Kobayashi, T., Stang, E., Fang, K.S., de Moerloose, P., Parton, R.G., and Gruenberg, J. (1998). A lipid associated with the antiphospholipid syndrome regulates endosome structure and function. Nature 392, 193–197.CrossRefGoogle Scholar
  33. Lahiri, S., Toulmay, A., and Prinz, W.A. (2015). Membrane contact sites, gateways for lipid homeostasis. Curr Opin Cell Biol 33, 82–87.CrossRefGoogle Scholar
  34. Lange, Y., Ye, J., and Chin, J. (1997). The fate of cholesterol exiting lysosomes. J Biol Chem 272, 17018–17022.CrossRefGoogle Scholar
  35. Liao, Y., Wei, J., Wang, J., Shi, X., Luo, J., and Song, B.L. (2018). The non-canonical NF-κB pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking. Sci China Life Sci 61, 1222–1232.CrossRefGoogle Scholar
  36. Liu, T.F., Tang, J.J., Li, P.S., Shen, Y., Li, J.G., Miao, H.H., Li, B.L., and Song, B.L. (2012). Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab 16, 213–225.CrossRefGoogle Scholar
  37. Luo, J., Jiang, L., Yang, H., and Song, B.L. (2017). Routes and mechanisms of post-endosomal cholesterol trafficking: A story that never ends. Traffic 18, 209–217.CrossRefGoogle Scholar
  38. Luo, J., Jiang, L.Y., Yang, H., and Song, B.L. (2019). Intracellular cholesterol transport by sterol transfer proteins at membrane contact sites. Trends Biochem Sci 44, 273–292.CrossRefGoogle Scholar
  39. Maximov, A., Lao, Y., Li, H., Chen, X., Rizo, J., Sørensen, J.B., and Südhof, T.C. (2008). Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis. Proc Natl Acad Sci USA 105, 3986–3991.CrossRefGoogle Scholar
  40. Moon, J.J., Suh, H., Bershteyn, A., Stephan, M.T., Liu, H., Huang, B., Sohail, M., Luo, S., Ho Um, S., Khant, H., et al. (2011). Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat Mater 10, 243–251.CrossRefGoogle Scholar
  41. Motley, A.M., and Hettema, E.H. (2007). Yeast peroxisomes multiply by growth and division. J Cell Biol 178, 399–410.CrossRefGoogle Scholar
  42. Neufeld, E.B., Cooney, A.M., Pitha, J., Dawidowicz, E.A., Dwyer, N.K., Pentchev, P.G., and Blanchette-Mackie, E.J. (1996). Intracellular trafficking of cholesterol monitored with a cyclodextrin. J Biol Chem 271, 21604–21613.CrossRefGoogle Scholar
  43. Novikoff, P.M., and Novikoff, A.B. (1972). Peroxisomes in absorptive cells of mammalian small intestine. J Cell Biol 53, 532–560.CrossRefGoogle Scholar
  44. Phillips, M.J., and Voeltz, G.K. (2016). Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol 17, 69–82.CrossRefGoogle Scholar
  45. Prabhu, A.V., Luu, W., Sharpe, L.J., and Brown, A.J. (2016). Cholesterol-mediated degradation of 7-Dehydrocholesterol reductase switches the balance from cholesterol to vitamin D synthesis. J Biol Chem 291, 8363–8373.CrossRefGoogle Scholar
  46. Radhakrishnan, A., Goldstein, J.L., McDonald, J.G., and Brown, M.S. (2008a). Switch-like control of SREBP-2 rransport rriggered by small changes in ER cholesterol: A delicate balance. Cell Metab 8, 512–521.CrossRefGoogle Scholar
  47. Radhakrishnan, A., Goldstein, J.L., McDonald, J.G., and Brown, M.S. (2008b). Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab 8, 512–521.CrossRefGoogle Scholar
  48. Raiborg, C., Wenzel, E.M., Pedersen, N.M., Olsvik, H., Schink, K.O., Schultz, S.W., Vietri, M., Nisi, V., Bucci, C., Brech, A., et al. (2015). Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth. Nature 520, 234–238.CrossRefGoogle Scholar
  49. Raychaudhuri, S., and Prinz, W.A. (2008). Nonvesicular phospholipid transfer between peroxisomes and the endoplasmic reticulum. Proc Natl Acad Sci USA 105, 15785–15790.CrossRefGoogle Scholar
  50. Russell, D.W. (2003). The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72, 137–174.CrossRefGoogle Scholar
  51. Saheki, Y. (2017). Endoplasmic Reticulum — Plasma Membrane Crosstalk Mediated by the Extended Synaptotagmins. Adv Exp Med Biol 997, 83–93.CrossRefGoogle Scholar
  52. Schrader, M., Reuber, B.E., Morrell, J.C., Jimenez-Sanchez, G., Obie, C., Stroh, T.A., Valle, D., Schroer, T.A., and Gould, S.J. (1998). Expression of PEX11 β Mediates Peroxisome Proliferation in the Absence of Extracellular Stimuli. J Biol Chem 273, 29607–29614.CrossRefGoogle Scholar
  53. Schuldiner, M., and Zalckvar, E. (2017). Incredibly close-A newly identified peroxisome-ER contact site in humans. J Cell Biol 216, 287–289.CrossRefGoogle Scholar
  54. Shai, N., Schuldiner, M., and Zalckvar, E. (2016). No peroxisome is an island-Peroxisome contact sites. BBA-Mol Cell Res 1863, 1061–1069.Google Scholar
  55. Sharpe, L.J., Cook, E.C.L., Zelcer, N., and Brown, A.J. (2014). The UPS and downs of cholesterol homeostasis. Trends Biochem Sci 39, 527–535.CrossRefGoogle Scholar
  56. Song, B.L., Sever, N., and DeBose-Boyd, R.A. (2005). Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell 19, 829–840.CrossRefGoogle Scholar
  57. Sugiura, A., Mattie, S., Prudent, J., and McBride, H.M. (2017). Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes. Nature 542, 251–254.CrossRefGoogle Scholar
  58. Tabak, H.F., Braakman, I., and van der Zand, A. (2013). Peroxisome formation and maintenance are dependent on the endoplasmic reticulum. Annu Rev Biochem 82, 723–744.CrossRefGoogle Scholar
  59. Underwood, K.W., Jacobs, N.L., Howley, A., and Liscum, L. (1998). Evidence for a cholesterol transport pathway from lysosomes to endoplasmic reticulum that is independent of the plasma membrane. J Biol Chem 273, 4266–4274.CrossRefGoogle Scholar
  60. van der Zand, A., Gent, J., Braakman, I., and Tabak, H.F. (2012). Biochemically distinct vesicles from the endoplasmic reticulum fuse to form peroxisomes. Cell 149, 397–409.CrossRefGoogle Scholar
  61. van Meer, G., Voelker, D.R., and Feigenson, G.W. (2008). Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9, 112–124.CrossRefGoogle Scholar
  62. Varnai, P., Thyagarajan, B., Rohacs, T., and Balla, T. (2006). Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells. J Cell Biol 175, 377–382.CrossRefGoogle Scholar
  63. Wang, J., Chu, B.B., Ge, L., Li, B.L., Yan, Y., and Song, B.L. (2009). Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. J Lipid Res 50, 1653–1662.CrossRefGoogle Scholar
  64. Wang, Y., Gao, J., Guo, X., Tong, T., Shi, X., Li, L., Qi, M., Wang, Y., Cai, M., Jiang, J., et al. (2014). Regulation of EGFR nanocluster formation by ionic protein-lipid interaction. Cell Res 24, 959–976.CrossRefGoogle Scholar
  65. Wang, Y.J., Bian, Y., Luo, J., Lu, M., Xiong, Y., Guo, S.Y., Yin, H.Y., Lin, X., Li, Q., Chang, C.C.Y., et al. (2017). Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol 19, 808–819.CrossRefGoogle Scholar
  66. Wong, Y.C., Ysselstein, D., and Krainc, D. (2018). Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386.CrossRefGoogle Scholar
  67. Zaar, K., Völkl, A., and Fahimi, H.D. (1987). Association of isolated bovine kidney cortex peroxisomes with endoplasmic reticulum. BBA-Biomembranes 897, 135–142.CrossRefGoogle Scholar
  68. Zhang, Y., Yu, C., Liu, J., Spencer, T.A., Chang, C.C.Y., and Chang, T.Y. (2003). Cholesterol Is Superior to 7-Ketocholesterol or 7α-Hydroxycholesterol as an Allosteric Activator for Acyl-coenzyme A: Cholesterol Acyltransferase 1. J Biol Chem 278, 11642–11647.CrossRefGoogle Scholar
  69. Zhao, K., and Ridgway, N.D. (2017). Oxysterol-binding protein-related protein 1L regulates cholesterol egress from the endo-lysosomal system. Cell Rep 19, 1807–1818.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jian Xiao
    • 1
  • Jie Luo
    • 1
  • Ao Hu
    • 1
  • Ting Xiao
    • 1
  • Meixin Li
    • 1
  • Zekai Kong
    • 1
  • Luyi Jiang
    • 1
  • Zimu Zhou
    • 1
  • Yacheng Liao
    • 2
  • Chang Xie
    • 2
  • Beibei Chu
    • 2
  • Honghua Miao
    • 2
  • Boliang Li
    • 2
  • Xiongjie Shi
    • 1
  • Bao-Liang Song
    • 1
    • 3
    Email author
  1. 1.College of Life Sciences, the Institute for Advanced StudiesWuhan UniversityWuhanChina
  2. 2.State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  3. 3.Shenzhen Institute of Wuhan UniversityShenzhenChina

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