Phosphatidylserine synthetase regulates cellular homeostasis through distinct metabolic mechanisms

Autoři: Xiao Yang aff001;  Jingjing Liang aff001;  Long Ding aff001;  Xia Li aff001;  Sin-Man Lam aff004;  Guanghou Shui aff001;  Mei Ding aff001;  Xun Huang aff001
Působiště autorů: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China aff001;  University of Chinese Academy of Sciences, Beijing, China aff002;  School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, TaiAn, China aff003;  LipidAll Technologies Co., Ltd. Changzhou, China aff004
Vyšlo v časopise: Phosphatidylserine synthetase regulates cellular homeostasis through distinct metabolic mechanisms. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008548
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008548


Phosphatidylserine (PS), synthesized in the endoplasmic reticulum (ER) by phosphatidylserine synthetase (PSS), is transported to the plasma membrane (PM) and mitochondria through distinct routes. The in vivo functions of PS at different subcellular locations and the coordination between different PS transport routes are not fully understood. Here, we report that Drosophila PSS regulates cell growth, lipid storage and mitochondrial function. In pss RNAi, reduced PS depletes plasma membrane Akt, contributing to cell growth defects; the metabolic shift from phospholipid synthesis to neutral lipid synthesis results in ectopic lipid accumulation; and the reduction of mitochondrial PS impairs mitochondrial protein import and mitochondrial integrity. Importantly, reducing PS transport from the ER to PM by loss of PI4KIIIα partially rescues the mitochondrial defects of pss RNAi. Together, our results uncover a balance between different PS transport routes and reveal that PSS regulates cellular homeostasis through distinct metabolic mechanisms.

Klíčová slova:

Cell growth – Cell membranes – Drosophila melanogaster – Lipids – Mitochondria – RNA interference – Salivary glands – Hormone transport


1. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, et al. (2012) Fat signals—lipases and lipolysis in lipid metabolism and signaling. Cell Metab 15:279–291. doi: 10.1016/j.cmet.2011.12.018 22405066

2. Vance JE (2008) Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49:1377–1387. doi: 10.1194/jlr.R700020-JLR200 18204094

3. Stone SJ, Vance JE (2000) Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J Biol Chem 275:34534–34540. doi: 10.1074/jbc.M002865200 10938271

4. Di Bartolomeo F, Wagner A, Daum G (2017) Cell biology, physiology and enzymology of phosphatidylserine decarboxylase. Biochim Biophys Acta Mol Cell Biol Lipids 1862:25–38. doi: 10.1016/j.bbalip.2016.09.007 27650064

5. Chung J, Torta F, Masai K, Lucast L, Czapla H, Tanner LB, et al. (2015) PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349:428–432. doi: 10.1126/science.aab1370 26206935

6. Moser von Filseck J, Copic A, Delfosse V, Vanni S, Jackson CL, Bourguet W, et al. (2015) Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349:432–436. doi: 10.1126/science.aab1346 26206936

7. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216. 1545126

8. Stone SJ, Vance JE (1999) Cloning and expression of murine liver phosphatidylserine synthase (PSS)-2: differential regulation of phospholipid metabolism by PSS1 and PSS2. Biochem J 342 (Pt 1):57–64.

9. Bergo MO, Gavino BJ, Steenbergen R, Sturbois B, Parlow AF, Sanan DA, et al. (2002) Defining the importance of phosphatidylserine synthase 2 in mice. J Biol Chem 277:47701–47708. doi: 10.1074/jbc.M207734200 12361952

10. Arikketh D, Nelson R, Vance JE (2008) Defining the importance of phosphatidylserine synthase-1 (PSS1): unexpected viability of PSS1-deficient mice. J Biol Chem 283:12888–12897. doi: 10.1074/jbc.M800714200 18343815

11. Kuge O, Saito K, Nishijima M (1997) Cloning of a Chinese hamster ovary (CHO) cDNA encoding phosphatidylserine synthase (PSS) II, overexpression of which suppresses the phosphatidylserine biosynthetic defect of a PSS I-lacking mutant of CHO-K1 cells. J Biol Chem 272:19133–19139. doi: 10.1074/jbc.272.31.19133 9235902

12. Kuge O, Nishijima M, Akamatsu Y (1991) A cloned gene encoding phosphatidylserine decarboxylase complements the phosphatidylserine biosynthetic defect of a Chinese hamster ovary cell mutant. J Biol Chem 266:6370–6376. 2007589

13. Kohlwein SD, Kuchler K, Sperka-Gottlieb C, Henry SA, Paltauf F (1988) Identification of mitochondrial and microsomal phosphatidylserine synthase in Saccharomyces cerevisiae as the gene product of the CHO1 structural gene. J Bacteriol 170:3778–3781. doi: 10.1128/jb.170.8.3778-3781.1988 2841305

14. Nikawa JI, Yamashita S (1981) Characterization of phosphatidylserine synthase from Saccharomyces cerevisiae and a mutant defective in the enzyme. Biochim Biophys Acta 665:420–426. doi: 10.1016/0005-2760(81)90254-x 6271228

15. Matsumoto A, Takahashi Y, Nishikawa M, Sano K, Morishita M, Charoenviriyakul C, et al. (2017) Role of phosphatidylserine-derived negative surface charges in the recognition and uptake of intravenously injected B16BL6-derived exosomes by macrophages. J Pharm Sci 106:168–175. doi: 10.1016/j.xphs.2016.07.022 27649887

16. Hildebrandt E, Khazanov N, Kappes JC, Dai Q, Senderowitz H, Urbatsch IL (2017) Specific stabilization of CFTR by phosphatidylserine. Biochim Biophys Acta Biomembr 1859:289–293. doi: 10.1016/j.bbamem.2016.11.013 27913277

17. Wijeyesakere SJ, Bedi SK, Huynh D, Raghavan M (2016) The C-terminal acidic region of calreticulin mediates phosphatidylserine binding and apoptotic cell phagocytosis. J Immunol 196:3896–3909. doi: 10.4049/jimmunol.1502122 27036911

18. Flis VV, Daum G (2013) Lipid transport between the endoplasmic reticulum and mitochondria. Cold Spring Harb Perspect Biol 5:1–23.

19. Jackson CL, Walch L, Verbavatz JM (2016) Lipids and their trafficking: an integral part of cellular organization. Dev Cell 39:139–153. doi: 10.1016/j.devcel.2016.09.030 27780039

20. Tatsuta T, Scharwey M, Langer T (2014) Mitochondrial lipid trafficking. Trends Cell Biol 24:44–52. doi: 10.1016/j.tcb.2013.07.011 24001776

21. Prinz WA (2010) Lipid trafficking sans vesicles: where, why, how? Cell 143:870–874. doi: 10.1016/j.cell.2010.11.031 21145454

22. Holthuis JC, Menon AK (2014) Lipid landscapes and pipelines in membrane homeostasis. Nature 510:48–57. doi: 10.1038/nature13474 24899304

23. Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, Antonny B (2013) A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155:830–843. doi: 10.1016/j.cell.2013.09.056 24209621

24. Im YJ, Raychaudhuri S, Prinz WA, Hurley JH (2005) Structural mechanism for sterol sensing and transport by OSBP-related proteins. Nature 437:154–158. doi: 10.1038/nature03923 16136145

25. Shiao YJ, Balcerzak B, Vance JE (1998) A mitochondrial membrane protein is required for translocation of phosphatidylserine from mitochondria-associated membranes to mitochondria. Biochem J 331:217–223. doi: 10.1042/bj3310217 9512482

26. Aaltonen MJ, Friedman JR, Osman C, Salin B, di Rago JP, Nunnari J, et al. (2016) MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J Cell Biol 213:525–534. doi: 10.1083/jcb.201602007 27241913

27. Miyata N, Watanabe Y, Tamura Y, Endo T, Kuge O (2016) Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria. J Cell Biol 214:77–88. doi: 10.1083/jcb.201601082 27354379

28. Tamura Y, Onguka O, Itoh K, Endo T, Iijima M, Claypool SM, et al. (2012) Phosphatidylethanolamine biosynthesis in mitochondria: phosphatidylserine (PS) trafficking is independent of a PS decarboxylase and intermembrane space proteins UPS1P and UPS2P. J Biol Chem 287:43961–43971. doi: 10.1074/jbc.M112.390997 23124206

29. Shiao YJ, Lupo G, Vance JE (1995) Evidence that phosphatidylserine is imported into mitochondria via a mitochondria-associated membrane and that the majority of mitochondrial phosphatidylethanolamine is derived from decarboxylation of phosphatidylserine. J Biol Chem 270:11190–11198. doi: 10.1074/jbc.270.19.11190 7744750

30. Liu Y, Wang W, Shui G, Huang X (2014) CDP-diacylglycerol synthetase coordinates cell growth and fat storage through phosphatidylinositol metabolism and the insulin pathway. PLoS Genet 10:e1004172. doi: 10.1371/journal.pgen.1004172 24603715

31. Britton JS, Lockwood WK, Li L, Cohen SM, Edgar BA (2002) Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell 2:239–249. doi: 10.1016/s1534-5807(02)00117-x 11832249

32. Huang BX, Akbar M, Kevala K, Kim HY (2011) Phosphatidylserine is a critical modulator for Akt activation. J Cell Biol 192:979–992. doi: 10.1083/jcb.201005100 21402788

33. Tasseva G, Bai HD, Davidescu M, Haromy A, Michelakis E, Vance JE (2013) Phosphatidylethanolamine deficiency in mammalian mitochondria impairs oxidative phosphorylation and alters mitochondrial morphology. J Biol Chem 288:4158–4173. doi: 10.1074/jbc.M112.434183 23250747

34. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125. doi: 10.1038/nature08778 20203611

35. LaJeunesse DR, Buckner SM, Lake J, Na C, Pirt A, Fromson K (2004) Three new Drosophila markers of intracellular membranes. BioTechniques 36:784–788, 790. doi: 10.2144/04365ST01 15152597

36. Laker RC, Xu P, Ryall KA, Sujkowski A, Kenwood BM, Chain KH, et al. (2014) A novel MitoTimer reporter gene for mitochondrial content, structure, stress, and damage in vivo. J Biol Chem 289:12005–12015. doi: 10.1074/jbc.M113.530527 24644293

37. Wiedemann N, Pfanner N (2017) Mitochondrial machineries for protein import and assembly. Annu Rev Biochem 86:685–714. doi: 10.1146/annurev-biochem-060815-014352 28301740

38. Liu W, Duan X, Fang X, Shang W, Tong C (2018) Mitochondrial protein import regulates cytosolic protein homeostasis and neuronal integrity. Autophagy 14:1293–1309. doi: 10.1080/15548627.2018.1474991 29909722

39. Bi J, Wang W, Liu Z, Huang X, Jiang Q, Liu G, et al. (2014) Seipin promotes adipose tissue fat storage through the ER Ca2+-ATPase SERCA. Cell Metab 19:861–871. doi: 10.1016/j.cmet.2014.03.028 24807223

40. Tan J, Oh K, Burgess J, Hipfner DR, Brill JA (2014) PI4KIIIα is required for cortical integrity and cell polarity during Drosophila oogenesis. J Cell Sci 127:954–966. doi: 10.1242/jcs.129031 24413170

41. Schmitt S, Ugrankar R, Greene SE, Prajapati M, Lehmann M (2015) Drosophila Lipin interacts with insulin and TOR signaling pathways in the control of growth and lipid metabolism. J Cell Sci 128:4395–4406. doi: 10.1242/jcs.173740 26490996

42. Takeuchi K, Reue K (2009) Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab 296:E1195–1209. doi: 10.1152/ajpendo.90958.2008 19336658

43. Dobrosotskaya IY, Seegmiller AC, Brown MS, Goldstein JL, Rawson RB (2002) Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science 296:879–883. doi: 10.1126/science.1071124 11988566

44. Fei W, Shui G, Zhang Y, Krahmer N, Ferguson C, Kapterian TS, et al. (2011) A role for phosphatidic acid in the formation of "supersized" lipid droplets. PLoS Genet 7:e1002201. doi: 10.1371/journal.pgen.1002201 21829381

45. MacVicar T, Ohba Y, Nolte H, Mayer FC, Tatsuta T, Sprenger HG, et al. (2019) Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature 575:361–365. doi: 10.1038/s41586-019-1738-6 31695197

46. Becker T, Horvath SE, Bottinger L, Gebert N, Daum G, Pfanner N (2013) Role of phosphatidylethanolamine in the biogenesis of mitochondrial outer membrane proteins. J Biol Chem 288:16451–16459. doi: 10.1074/jbc.M112.442392 23625917

47. Eilers M, Endo T, Schatz G (1989) Adriamycin, a drug interacting with acidic phospholipids, blocks import of precursor proteins by isolated yeast mitochondria. J Biol Chem 264:2945–2950. 2644274

48. Jiang F, Ryan MT, Schlame M, Zhao M, Gu Z, Klingenberg M, et al. (2000) Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function. J Biol Chem 275:22387–22394. doi: 10.1074/jbc.M909868199 10777514

49. Friedman JR, Kannan M, Toulmay A, Jan CH, Weissman JS, Prinz WA, et al. (2018) Lipid homeostasis is maintained by dual targeting of the mitochondrial PE biosynthesis enzyme to the ER. Dev Cell 44:261–270 e266. doi: 10.1016/j.devcel.2017.11.023 29290583

50. Fairn GD, Schieber NL, Ariotti N, Murphy S, Kuerschner L, Webb RI, et al. (2011) High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J Cell Biol 194:257–275. doi: 10.1083/jcb.201012028 21788369

51. Ding L, Yang X, Tian H, Liang J, Zhang F, Wang G, et al. (2018) Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism. EMBO J 37:e97572. doi: 10.15252/embj.201797572 30049710

52. El-Gebali S, Mistry J, Bateman A, Eddy SR, Luciani A, Potter SC, et al. (2019) The Pfam protein families database in 2019. Nucleic Acids Res 47:D427–D432. doi: 10.1093/nar/gky995 30357350

53. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S (2013) MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 30:2725–2729. doi: 10.1093/molbev/mst197 24132122

54. Tamura Y, Harada Y, Nishikawa S, Yamano K, Kamiya M, Shiota T, et al. (2013) Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria. Cell Metab 17:709–718. doi: 10.1016/j.cmet.2013.03.018 23623749

55. Lam SM, Wang Y, Duan X, Wenk MR, Kalaria RN, Chen CP, et al. (2014) The brain lipidomes of subcortical ischemic vascular dementia and mixed dementia. Neurobiol Aging 35:2369–2381. doi: 10.1016/j.neurobiolaging.2014.02.025 24684787

Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics

2019 Číslo 12

Nejčtenější v tomto čísle
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se