SpringerLink
Log in

Role of PI(4,5)P2 and Cholesterol in Unconventional Protein Secretion

  • Chapter
  • First Online:
Cholesterol and PI(4,5)P2 in Vital Biological Functions

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1422))

  • 671 Accesses

Abstract

Besides its protective role in the maintenance of cell homeostasis, the plasma membrane is the site of exchanges between the cell interior and the extracellular medium. To circumvent the hydrophobic barrier formed by the acyl chains of the lipid bilayer, protein channels and transporters are key players in the exchange of small hydrophilic compounds such as ions or nutrients, but they hardly account for the transport of larger biological molecules. Exchange of proteins usually relies on membrane-fusion events between vesicles and the plasma membrane. In recent years, several alternative unconventional protein secretion (UPS) pathways across the plasma membrane have been characterised for a specific set of secreted substrates, some of them excluding any membrane-fusion events (Dimou and Nickel, Curr Biol 28:R406–R410, 2018). One of thesbe pathways, referred as type I UPS, relies on the direct translocation of the protein across the plasma membrane and not surprisingly, lipids are essential players in this process. In this chapter, we discuss the roles of phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and cholesterol in unconventional pathways involving Engrailed-2 homeoprotein and fibroblast growth factor 2.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CPP:

cell penetrating peptides

EN2:

Engrailed-2 homeoprotein

ER:

endoplasmic reticulum

FGF2:

fibroblast growth factor 2

FITC:

fluorescein isothiocyanate

HIV:

human immunodeficiency virus

IP:

inositol phosphate

PC:

phosphatidylcholine

PG:

phosphatidylglycerol

PHPLC:

Pleckstrin homology domain of phospholipase C ∂

PI(4)P:

phosphatidylinositol(4)phosphate

PI(4,5)P2:

phosphatidylinositol(4,5)bisphosphate

PS:

phosphatidylserine

RUSH:

retention using selective hook

SRP:

signal recognition particle

UPS:

unconventional protein secretion

References

  1. Dimou E, Nickel W. Unconventional mechanisms of eukaryotic protein secretion. Curr Biol. 2018;28:R406–10.

    Article  CAS  PubMed  Google Scholar 

  2. Holland PW, Booth HAF, Bruford EA. Classification and nomenclature of all human homeobox genes. BMC Biol. 2007;5:47.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Affolter M, Schier A, Gehring WJ. Homeodomain proteins and the regulation of gene expression. Curr Opin Cell Biol. 1990;2:485–95.

    Article  CAS  PubMed  Google Scholar 

  4. Hunt P, Krumlauf R. Hox codes and positional specification in vertebrate embryonic axes. Annu Rev Cell Biol. 1992;8:227–56.

    Article  CAS  PubMed  Google Scholar 

  5. Gehring WJ. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147–73.

    Article  CAS  PubMed  Google Scholar 

  6. Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci U S A. 1991;88:1864–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Joliot A, Triller A, Volovitch M, Pernelle C, Prochiantz A. alpha-2,8-Polysialic acid is the neuronal surface receptor of antennapedia homeobox peptide. New Biol. 1991;3:1121–34.

    CAS  PubMed  Google Scholar 

  8. Joliot A, Maizel A, Rosenberg D, Trembleau A, Dupas S, Volovitch M, Prochiantz A. Identification of a signal sequence necessary for the unconventional secretion of Engrailed homeoprotein. Curr Biol. 1998;8:856–63.

    Article  CAS  PubMed  Google Scholar 

  9. Dupont E, Prochiantz A, Joliot A. Identification of a signal peptide for unconventional secretion. J Biol Chem. 2007;282:8994–9000.

    Article  CAS  PubMed  Google Scholar 

  10. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269:10444–50.

    Article  CAS  PubMed  Google Scholar 

  11. Lee EJ, Kim N, Park JW, Kang KH, Kim W-I, Sim NS, Jeong C-S, Blackshaw S, Vidal M, Huh S-O, Kim D, et al. Global analysis of intercellular homeodomain protein transfer. Cell Rep. 2019;28:712–722.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Di Nardo AA, Fuchs J, Joshi RL, Moya KL, Prochiantz A. The physiology of homeoprotein transduction. Physiol Rev. 2018;98:1943–82.

    Article  CAS  PubMed  Google Scholar 

  13. Wizenmann A, Brunet I, Lam JSY, Sonnier L, Beurdeley M, Zarbalis K, Weisenhorn-Vogt D, Weinl C, Dwivedy A, Joliot A, Wurst W, et al. Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo. Neuron. 2009;64:355–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kaddour H, Coppola E, Di Nardo AA, Le Poupon C, Mailly P, Wizenmann A, Volovitch M, Prochiantz A, Pierani A. Extracellular Pax6 regulates tangential Cajal–Retzius cell migration in the develo** mouse neocortex. Cereb Cortex. 2020;30:465–75.

    CAS  PubMed  Google Scholar 

  15. Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK. Experience-dependent transfer of Otx2 Homeoprotein into the visual cortex activates postnatal plasticity. Cell. 2008;134:508–20.

    Article  CAS  PubMed  Google Scholar 

  16. Layalle S, Volovitch M, Mugat B, Bonneaud N, Parmentier M-L, Prochiantz A, Joliot A, Maschat F. Engrailed homeoprotein acts as a signaling molecule in the develo** fly. Development. 2011;138:2315–23.

    Article  CAS  PubMed  Google Scholar 

  17. Rampon C, Gauron C, Lin T, Meda F, Dupont E, Cosson A, Ipendey E, Frerot A, Aujard I, Le Saux T, Bensimon D, et al. Control of brain patterning by Engrailed paracrine transfer: a new function of the Pbx interaction domain. Development. 2015;142:1840–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lindgren ME, Hällbrink MM, Prochiantz A, Langel U. Cell-penetrating peptides. Trends Pharmacol Sci. 2000;21:99–103.

    Article  CAS  PubMed  Google Scholar 

  19. Christiaens B, Symoens S, Verheyden S, Engelborghs Y, Joliot A, Prochiantz A, Vandekerckhove J, Rosseneu M, Vanloo B, Vanderheyden S. Tryptophan fluorescence study of the interaction of penetratin peptides with model membranes. Eur J Biochem. 2002;269:2918–26.

    Article  CAS  PubMed  Google Scholar 

  20. Drin G, Mazel M, Clair P, Mathieu D, Kaczorek M, Temsamani J. Physico-chemical requirements for cellular uptake of pAntp peptide. Role of lipid-binding affinity. Eur J Biochem. 2001;268:1304–14.

    Article  CAS  PubMed  Google Scholar 

  21. Binder H, Lindblom G. Charge-dependent translocation of the Trojan peptide penetratin across lipid membranes. Biophys J. 2003;85:982–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Magzoub M, Eriksson LEG, Gräslund A. Conformational states of the cell-penetrating peptide penetratin when interacting with phospholipid vesicles: effects of surface charge and peptide concentration. Biochim Biophys Acta. 2002;1563:53–63.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang W, Smith SO. Mechanism of penetration of Antp(43-58) into membrane bilayers. Biochemistry. 2005;44:10110–8.

    Article  CAS  PubMed  Google Scholar 

  24. Amand HL, Boström CL, Lincoln P, Nordén B, Esbjörner EK. Binding of cell-penetrating penetratin peptides to plasma membrane vesicles correlates directly with cellular uptake. Biochim Biophys Acta. 2011;1808:1860–7.

    Article  CAS  PubMed  Google Scholar 

  25. Maniti O, Blanchard E, Trugnan G, Lamazière A, Ayala-Sanmartin J. Metabolic energy-independent mechanism of internalization for the cell penetrating peptide penetratin. Int J Biochem Cell Biol. 2012;44:869–75.

    Article  CAS  PubMed  Google Scholar 

  26. Terrone D, Sang SLW, Roudaia L, Silvius JR. Penetratin and related cell-penetrating cationic peptides can translocate across lipid bilayers in the presence of a transbilayer potential. Biochemistry. 2003;42:13787–99.

    Article  CAS  PubMed  Google Scholar 

  27. Clarke ND, Kissinger CR, Desjarlais J, Gilliland GL, Pabo CO. Structural studies of the engrailed homeodomain. Protein Sci. 1994;3:1779–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Müller M, Gehring WJ. The structure of the Antennapedia homeodomain determined by NMR spectroscopy in solution: comparison with prokaryotic repressors. Cell. 1989;59:573–80.

    Article  PubMed  Google Scholar 

  29. Carlier L, Balayssac S, Cantrelle F-X, Khemtémourian L, Chassaing G, Joliot A, Lequin O. Investigation of homeodomain membrane translocation properties: insights from the structure determination of engrailed-2 homeodomain in aqueous and membrane-mimetic environments. Biophys J. 2013;105:667–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Joliot A, Trembleau A, Raposo G, Calvet S, Volovitch M, Prochiantz A. Association of Engrailed homeoproteins with vesicles presenting caveolae-like properties. Development. 1997;124:1865–75.

    Article  CAS  PubMed  Google Scholar 

  31. Tassetto M, Maizel A, Osorio J, Joliot A. Plant and animal homeodomains use convergent mechanisms for intercellular transfer. EMBO Rep. 2005;6:885–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Florkiewicz RZ, Florkiewicz RZ, Majack RA, Majack RA, Buechler RD, Buechler RD, Florkiewicz E, Florkiewicz E. Quantitative export of FGF-2 occurs through an alternative, energy-dependent, non-ER/Golgi pathway. J Cell Physiol. 1995;162:388–99.

    Article  CAS  PubMed  Google Scholar 

  33. Schäfer T, Zentgraf H, Zehe C, Brügger B, Bernhagen J, Nickel W. Unconventional secretion of fibroblast growth factor 2 is mediated by direct translocation across the plasma membrane of mammalian cells. J Biol Chem. 2004;279:6244–51.

    Article  PubMed  Google Scholar 

  34. Temmerman K, Ebert AD, Müller H-M, Sinning I, Tews I, Nickel W. A direct role for phosphatidylinositol-4,5-bisphosphate in unconventional secretion of fibroblast growth factor 2. Traffic. 2008;9:1204–17.

    Article  CAS  PubMed  Google Scholar 

  35. Torrado LC, Temmerman K, Müller H-M, Mayer MP, Seelenmeyer C, Backhaus R, Nickel W. An intrinsic quality-control mechanism ensures unconventional secretion of fibroblast growth factor 2 in a folded conformation. J Cell Sci. 2009;122:3322–9.

    Article  CAS  PubMed  Google Scholar 

  36. Rayne F, Debaisieux S, Yezid H, Lin Y-L, Mettling C, Konate K, Chazal N, Arold ST, Pugnière M, Sanchez F, Bonhoure A, et al. Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J. 2010;29:1348–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Várnai P, Balla T. Visualization of phosphoinositides that bind pleckstrin homology domains: calcium- and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools. J Cell Biol. 1998;143:501–10.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Amblard I, Dupont E, Alves I, Miralvès J, Queguiner I, Joliot A. Bidirectional transfer of homeoprotein EN2 across the plasma membrane requires PIP2. J Cell Sci. 2020; https://doi.org/10.1242/jcs.244327.

  39. Boncompain G, Divoux S, Gareil N, de Forges H, Lescure A, Latreche L, Mercanti V, Jollivet F, Raposo G, Perez F. Synchronization of secretory protein traffic in populations of cells. Nat Methods. 2012;9:493–8.

    Article  CAS  PubMed  Google Scholar 

  40. Dixon AS, Schwinn MK, Hall MP, Zimmerman K, Otto P, Lubben TH, Butler BL, Binkowski BF, Machleidt T, Kirkland TA, Wood MG, et al. NanoLuc complementation reporter optimized for accurate measurement of protein interactions in cells. ACS Chem Biol. 2016;11:400–8.

    Article  CAS  PubMed  Google Scholar 

  41. Harté E, Maalouli N, Shalabney A, Texier E, Berthelot K, Lecomte S, Alves ID. Probing the kinetics of lipid membrane formation and the interaction of a nontoxic and a toxic amyloid with plasmon waveguide resonance. Chem Commun (Camb). 2014;50:4168–71.

    Article  PubMed  Google Scholar 

  42. Amblard I, Thauvin M, Rampon C, Queguiner I, Pak VV, Belousov V, Prochiantz A, Volovitch M, Joliot A, Vriz S. H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum. Commun Biol. 2020;3:536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bidlingmaier S, Wang Y, Liu Y, Zhang N, Liu B. Comprehensive analysis of yeast surface displayed cDNA library selection outputs by exon microarray to identify novel protein-ligand interactions. Mol Cell Proteomics. 2011;10:M110.005116-M110.005116.

    Article  Google Scholar 

  44. Zacherl S, La Venuta G, Müller H-M, Wegehingel S, Dimou E, Sehr P, Lewis JD, Erfle H, Pepperkok R, Nickel W. A direct role for ATP1A1 in unconventional secretion of fibroblast growth factor 2. J Biol Chem. 2015;290:3654–65.

    Article  CAS  PubMed  Google Scholar 

  45. Steringer JP, Nickel W. The molecular mechanism underlying unconventional secretion of fibroblast growth factor 2 from tumour cells. Biol Cell. 2017;117:1727.

    Google Scholar 

  46. Zeitler M, Steringer JP, Müller H-M, Mayer MP, Nickel W. HIV-tat protein forms phosphoinositide-dependent membrane pores implicated in unconventional protein secretion. J Biol Chem. 2015;290:21976–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Müller H-M, Steringer JP, Wegehingel S, Bleicken S, Münster M, Dimou E, Unger S, Weidmann G, Andreas H, García-Sáez AJ, Wild K, et al. Formation of disulfide bridges drives oligomerization, membrane pore formation and translocation of fibroblast growth factor 2 to cell surfaces. J Biol Chem. 2015;290:8925–37.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Steringer JP, Bleicken S, Andreas H, Zacherl S, Laussmann M, Temmerman K, Contreras FX, Bharat TAM, Lechner J, Müller H-M, Briggs JAG, et al. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent oligomerization of fibroblast growth factor 2 (FGF2) triggers the formation of a lipidic membrane pore implicated in unconventional secretion. J Biol Chem. 2012;287:27659–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Beurdeley M, Spatazza J, Lee HHC, Sugiyama S, Bernard C, Di Nardo AA, Hensch TK, Prochiantz A. Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci. 2012;32:9429–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang Y-H, Bucki R, Janmey PA. Cholesterol-dependent phase-demixing in lipid bilayers as a switch for the activity of the phosphoinositide-binding cytoskeletal protein gelsolin. Biochemistry. 2016;55:3361–9.

    Article  CAS  PubMed  Google Scholar 

  51. Jiang Z, Redfern RE, Isler Y, Ross AH, Gericke A. Cholesterol stabilizes fluid phosphoinositide domains. Chem Phys Lipids. 2014;182:52–61.

    Article  CAS  PubMed  Google Scholar 

  52. van Rheenen J, Mulugeta Achame E, Janssen H, Calafat J, Jalink K. PIP2 signaling in lipid domains: a critical re-evaluation. EMBO J. 2005;24:1664–73.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Myeong J, Park C-G, Suh B-C, Hille B. Compartmentalization of phosphatidylinositol 4,5-bisphosphate metabolism into plasma membrane liquid-ordered/raft domains. PNAS. 2021; https://doi.org/10.1073/pnas.2025343118.

  54. Fujita A, Cheng J, Tauchi-Sato K, Takenawa T, Fujimoto T. A distinct pool of phosphatidylinositol 4,5-bisphosphate in caveolae revealed by a nanoscale labeling technique. Proc Natl Acad Sci U S A. 2009;106:9256–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang S-T, Kiessling V, Tamm LK. Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion. Nat Commun. 2016;7:11401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tryoen-Tóth P, Chasserot-Golaz S, Tu A, Gherib P, Bader M-F, Beaumelle B, Vitale N. HIV-1 Tat protein inhibits neurosecretion by binding to phosphatidylinositol 4,5-bisphosphate. J Cell Sci. 2013;126:454–63.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. INSERM U932, Institut Curie Centre de Recherche, PSL Research University, Paris, France

    Alain Joliot

Authors
  1. Alain Joliot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alain Joliot .

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA

    Avia Rosenhouse- Dantsker

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Joliot, A. (2023). Role of PI(4,5)P2 and Cholesterol in Unconventional Protein Secretion. In: Dantsker, A.R. (eds) Cholesterol and PI(4,5)P2 in Vital Biological Functions. Advances in Experimental Medicine and Biology, vol 1422. Springer, Cham. https://doi.org/10.1007/978-3-031-21547-6_14

Download citation

Publish with us

Policies and ethics

Search

Navigation