Current Genetics

, Volume 65, Issue 1, pp 57–64 | Cite as

From underlying chemistry to therapeutic potential: open questions in the new field of lysine polyphosphorylation

  • Amanda Bentley-DeSousa
  • Michael DowneyEmail author


Polyphosphorylation is a newly described non-enzymatic post-translational modification wherein long chains of inorganic phosphates are attached to lysine residues. The first targets of polyphosphorylation identified were S. cerevisiae proteins Nsr1 and Top1. Building on this theme, we recently exploited functional genomics tools in yeast to identify 15 new targets, including a conserved network of nucleolar proteins implicated in ribosome biogenesis. We also described the polyphosphorylation of six human proteins, suggesting that this unique post-translational modification could be conserved throughout eukaryotes. The study of polyphosphorylation seems poised to uncover novel modes of protein regulation in pathways spanning diverse biological processes. In this review, we establish a framework for future work by outlining critical questions related to the biochemistry of polyphosphorylation, its therapeutic potential, and everything in between.


PolyP Lysine polyphosphorylation Ppn1 Ppn2 Ppx1 Vtc4 EcPPK1 



We thank the members of the Downey lab for critical review of the manuscript. Polyphosphate work in the Downey lab is funded by the Canadian Institutes of Health Research (PJT-148722).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts.


  1. Andreeva N, Trilisenko L, Eldarov M, Kulakovskaya T (2015) Polyphosphatase PPN1 of Saccharomyces cerevisiae: switching of exopolyphosphatase and endopolyphosphatase activities. PLoS One 10:e0119594. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arelaki S, Arampatzioglou A, Kambas K, Sivridis E, Giatromanolaki A, Ritis K (2018) Mast cells co-expressing CD68 and inorganic polyphosphate are linked with colorectal cancer. PLoS One 13:e0193089. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Auesukaree C, Homma T, Tochio H, Shirakawa M, Kaneko Y, Harashima S (2004) Intracellular phosphate serves as a signal for the regulation of the PHO pathway in Saccharomyces cerevisiae. J Biol Chem 279:17289–17294. CrossRefPubMedGoogle Scholar
  4. Azevedo C, Saiardi A (2015) Why always lysine? The ongoing tale of one of the most modified amino acids. Adv Biol Regul. CrossRefPubMedGoogle Scholar
  5. Azevedo C, Livermore T, Saiardi A (2015) Protein polyphosphorylation of lysine residues by inorganic. polyphosphate Mol Cell 58:71–82. CrossRefPubMedGoogle Scholar
  6. Bae JS, Lee W, Rezaie AR (2012) Polyphosphate elicits pro-inflammatory responses that are counteracted by activated protein C in both cellular and animal models. J Thromb Haemost 10:1145–1151. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bashatwah RM, Khanfar MA, Bardaweel SK (2018) Discovery of potent polyphosphate kinase 1 (PPK1) inhibitors using structure-based exploration of PPK1Pharmacophoric space coupled with docking analyses. J Mol Recognit:e2726. CrossRefGoogle Scholar
  8. Bentley-DeSousa A et al (2018) A screen for candidate targets of lysine polyphosphorylation uncovers a conserved network implicated in ribosome biogenesis. Cell Rep 22:3427–3439. CrossRefPubMedGoogle Scholar
  9. Bru S et al (2016) Polyphosphate is involved in cell cycle progression and genomic stability in Saccharomyces cerevisiae. Mol Microbiol 101:367–380. CrossRefPubMedGoogle Scholar
  10. Cai L, Sutter BM, Li B, Tu BP (2011) Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell 42:426–437. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Choi SH, Smith SA, Morrissey JH (2011) Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 118:6963–6970. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Choi SH, Smith SA, Morrissey JH (2015) Polyphosphate accelerates factor V activation by factor XIa. Thromb Haemost 113:599–604. CrossRefPubMedGoogle Scholar
  13. Cremers CM et al (2016) Polyphosphate: a conserved modifier of amyloidogenic processes. Mol Cell 63:768–780. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dahl JU et al (2017) The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. Nat Microbiol 2:16267. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Desfougeres Y, Gerasimaite RU, Jessen HJ, Mayer A (2016) Vtc5, a novel subunit of the vacuolar transporter chaperone complex, regulates polyphosphate synthesis and phosphate homeostasis in yeast. J Biol Chem 291:22262–22275. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Donovan AJ et al (2016) Artificial dense granules: a procoagulant liposomal formulation modeled after platelet polyphosphate storage pools. Biomacromolecules 17:2572–2581. CrossRefPubMedGoogle Scholar
  17. Eskes E, Deprez MA, Wilms T, Winderickx J (2018) pH homeostasis in yeast; the phosphate perspective. Curr Genet 64:155–161. CrossRefPubMedGoogle Scholar
  18. Freimoser FM, Hurlimann HC, Jakob CA, Werner TP, Amrhein N (2006) Systematic screening of polyphosphate (poly P) levels in yeast mutant cells reveals strong interdependence with primary metabolism. Genome Biol 7:R109. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gerasimaite R, Mayer A (2017) Ppn2, a novel Zn(2+)-dependent polyphosphatase in the acidocalcisome-like yeast vacuole. J Cell Sci 130:1625–1636. CrossRefPubMedGoogle Scholar
  20. Gerasimaite R, Sharma S, Desfougeres Y, Schmidt A, Mayer A (2014) Coupled synthesis and translocation restrains polyphosphate to acidocalcisome-like vacuoles and prevents its toxicity. J Cell Sci 127:5093–5104. CrossRefPubMedGoogle Scholar
  21. Gray MJ et al (2014) Polyphosphate is a primordial chaperone. Mol Cell 53:689–699. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hacchou Y et al (2007) Inorganic polyphosphate: a possible stimulant of bone formation. J Dent Res 86:893–897. CrossRefPubMedGoogle Scholar
  23. Hardman G et al. (2017) Extensive non-canonical phosphorylation in human cells revealed using strong-anion exchange-mediated phosphoproteomics. bioRxiv CrossRefGoogle Scholar
  24. Hernandez-Ruiz L, Gonzalez-Garcia I, Castro C, Brieva JA, Ruiz FA (2006) Inorganic polyphosphate and specific induction of apoptosis in human plasma cells. Haematologica 91:1180–1186PubMedGoogle Scholar
  25. Hoac B, Kiffer-Moreira T, Millan JL, McKee MD (2013) Polyphosphates inhibit extracellular matrix mineralization in MC3T3-E1 osteoblast cultures. Bone 53:478–486. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Holmstrom KM, Marina N, Baev AY, Wood NW, Gourine AV, Abramov AY (2013) Signalling properties of inorganic polyphosphate in the mammalian brain. Nat Commun 4:1362. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hothorn M et al (2009) Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase. Science 324:513–516. CrossRefPubMedGoogle Scholar
  28. Jimenez J, Bru S, Ribeiro MP, Clotet J (2017) Polyphosphate: popping up from oblivion. Curr Genet 63:15–18. CrossRefPubMedGoogle Scholar
  29. Jimenez-Nunez MD et al (2012) Myeloma cells contain high levels of inorganic polyphosphate which is associated with nucleolar transcription. Haematologica 97:1264–1271. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kim KS, Rao NN, Fraley CD, Kornberg A (2002) Inorganic polyphosphate is essential for long-term survival and virulence factors in Shigella and Salmonella spp. Proc Natl Acad Sci USA 99:7675–7680. CrossRefPubMedGoogle Scholar
  31. Kornberg A, Rao NN, Ault-Riche D (1999) Inorganic polyphosphate: a molecule of many functions. Annu Rev Biochem 68:89–125. CrossRefPubMedGoogle Scholar
  32. Kumble KD, Kornberg A (1995) Inorganic polyphosphate in mammalian cells and tissues. J Biol Chem 270:5818–5822CrossRefPubMedGoogle Scholar
  33. Labberton L et al (2016) Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 7:12616. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lichko LP, Kulakovskaya TV, Kulaev IS (2006) Inorganic polyphosphate and exopolyphosphatase in the nuclei of Saccharomyces cerevisiae: dependence on the growth phase and inactivation of the PPX1 and PPN1 genes. Yeast 23:735–740. CrossRefPubMedGoogle Scholar
  35. Lonetti A, Szijgyarto Z, Bosch D, Loss O, Azevedo C, Saiardi A (2011) Identification of an evolutionarily conserved family of inorganic polyphosphate endopolyphosphatases. J Biol Chem 286:31966–31974. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Mitchell JL, Lionikiene AS, Georgiev G, Klemmer A, Brain C, Kim PY, Mutch NJ (2016) Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity. Blood 128:2834–2845. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Moreno SN, Docampo R (2013) Polyphosphate and its diverse functions in host cells and pathogens. PLoS Pathog 9:e1003230. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Morrissey JH, Choi SH, Smith SA (2012) Polyphosphate: an ancient molecule that links platelets, coagulation and inflammation. Blood 119:5972–5979. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Muhl L et al (2009) High negative charge-to-size ratio in polyphosphates and heparin regulates factor VII-activating protease. FEBS J 276:4828–4839. CrossRefPubMedGoogle Scholar
  40. Muller F et al (2009) Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139:1143–1156. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Mutch NJ, Engel R, Uitte de Willige S, Philippou H, Ariens RA (2010a) Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood 115:3980–3988 CrossRefPubMedGoogle Scholar
  42. Mutch NJ, Myles T, Leung LL, Morrissey JH (2010b) Polyphosphate binds with high affinity to exosite II of thrombin. J Thromb Haemost 8:548–555. CrossRefPubMedGoogle Scholar
  43. Peng L et al (2016) Involvement of polyphosphate kinase in virulence and stress tolerance of uropathogenic Proteus mirabilis. Med Microbiol Immunol 205:97–109. CrossRefPubMedGoogle Scholar
  44. Puy C et al (2013) Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. J Thromb Haemost 11:1341–1352. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Puy C et al (2016) Platelet-derived short-chain polyphosphates enhance the inactivation of tissue factor pathway inhibitor by activated coagulation factor XI. PLoS One 11:e0165172. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Rao NN, Gomez-Garcia MR, Kornberg A (2009) Inorganic polyphosphate: essential for growth and survival. Annu Rev Biochem 78:605–647. CrossRefGoogle Scholar
  47. Rashid MH, Kornberg A (2000) Inorganic polyphosphate is needed for swimming, swarming, and twitching motilities of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 97:4885–4890. CrossRefPubMedGoogle Scholar
  48. Rashid MH, Rao NN, Kornberg A (2000a) Inorganic polyphosphate is required for motility of bacterial pathogens. J Bacteriol 182:225–227CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rashid MH, Rumbaugh K, Passador L, Davies DG, Hamood AN, Iglewski BH, Kornberg A (2000b) Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 97:9636–9641. CrossRefPubMedGoogle Scholar
  50. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–S17. CrossRefGoogle Scholar
  51. Ruiz FA, Lea CR, Oldfield E, Docampo R (2004) Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem 279:44250–44257. CrossRefPubMedGoogle Scholar
  52. Saito K, Ohtomo R, Kuga-Uetake Y, Aono T, Saito M (2005) Direct labeling of polyphosphate at the ultrastructural level in Saccharomyces cerevisiae by using the affinity of the polyphosphate binding domain of Escherichia coli exopolyphosphatase. Appl Environ Microbiol 71:5692–5701. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shiba T et al (1997) Inorganic polyphosphate and the induction of rpoS expression. Proc Natl Acad Sci USA 94:11210–11215CrossRefPubMedGoogle Scholar
  54. Smith SA, Morrissey JH (2008) Polyphosphate enhances fibrin clot structure. Blood 112:2810–2816. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH (2006) Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 103:903–908. CrossRefPubMedGoogle Scholar
  56. Smith SA, Choi SH, Davis-Harrison R, Huyck J, Boettcher J, Rienstra CM, Morrissey JH (2010) Polyphosphate exerts differential effects on blood clotting depending on polymer size. Blood 116:4353–4359. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH (2012) Inhibition of polyphosphate as a novel strategy for preventing thrombosis. and inflammation. Blood 120:5103–5110. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Stotz SC et al (2014) Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. Mol Brain 7:42. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Tammenkoski M, Koivula K, Cusanelli E, Zollo M, Steegborn C, Baykov AA, Lahti R (2008) Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase. Biochemistry 47:9707–9713. CrossRefPubMedGoogle Scholar
  60. Tsutsumi K et al (2017) Inorganic polyphosphate enhances radio-sensitivity in a human non-small cell lung cancer cell line H1299. Tumour Biol 39:1010428317705033. CrossRefPubMedGoogle Scholar
  61. Usui Y et al (2010) Inorganic polyphosphate induces osteoblastic differentiation. J Dent Res 89:504–509. CrossRefPubMedGoogle Scholar
  62. Wang L, Fraley CD, Faridi J, Kornberg A, Roth RA (2003) Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells. Proc Natl Acad Sci USA 100:11249–11254. CrossRefPubMedGoogle Scholar
  63. Wat JM et al (2014) Polyphosphate suppresses complement via the terminal pathway. Blood 123:768–776. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Weinert BT et al (2014) Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. Mol Syst Biol 10:716. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Whyte CS, Chernysh IN, Domingues MM, Connell S, Weisel JW, Ariens RA, Mutch NJ (2016) Polyphosphate delays fibrin polymerisation and alters the mechanical properties of the fibrin network. Thromb Haemost 116:897–903. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cellular and Molecular MedicineUniversity of OttawaOttawaCanada
  2. 2.Ottawa Institute of Systems BiologyUniversity of OttawaOttawaCanada

Personalised recommendations