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Cellular and Molecular Life Sciences

, Volume 73, Issue 24, pp 4717–4737 | Cite as

PIKfyve inhibition increases exosome release and induces secretory autophagy

  • Nina Pettersen Hessvik
  • Anders Øverbye
  • Andreas Brech
  • Maria Lyngaas Torgersen
  • Ida Seim Jakobsen
  • Kirsten Sandvig
  • Alicia LlorenteEmail author
Original Article

Abstract

Exosomes are vesicles released from cells by fusion of multivesicular bodies (MVBs) with the plasma membrane. This study aimed to investigate whether the phosphoinositide kinase PIKfyve affects this process. Our results show that in PC-3 cells inhibition of PIKfyve by apilimod or depletion by siRNA increased the secretion of the exosomal fraction. Moreover, quantitative electron microscopy analysis showed that cells treated with apilimod contained more MVBs per cell and more intraluminal vesicles per MVB. Interestingly, mass spectrometry analysis revealed a considerable enrichment of autophagy-related proteins (NBR1, p62, LC3, WIPI2) in exosomal fractions released by apilimod-treated cells, a result that was confirmed by immunoblotting. When the exosome preparations were investigated by electron microscopy a small population of p62-labelled electron dense structures was observed together with CD63-containing exosomes. The p62-positive structures were found in less dense fractions than exosomes in density gradients. Inside the cells, p62 and CD63 were found in the same MVB-like organelles. Finally, both the degradation of EGF and long-lived proteins were shown to be reduced by apilimod. In conclusion, inhibition of PIKfyve increases secretion of exosomes and induces secretory autophagy, showing that these pathways are closely linked. We suggest this is due to impaired fusion of lysosomes with both MVBs and autophagosomes, and possibly increased fusion of MVBs with autophagosomes, and that the cells respond by secreting the content of these organelles to maintain cellular homeostasis.

Keywords

Exosomes Extracellular vesicles PIKfyve Secretory autophagy Exophagy Phosphoinositides 

Abbreviations

CI-MPR

Cation-independent mannose 6-phosphate receptor

EM

Electron microscopy

ESCRTs

Endosomal sorting complexes required for transport proteins

ILV

Intraluminal vesicle

MS

Mass spectrometry

MVB

Multivesicular body

NTA

Nanoparticle tracking analysis

PI(3)P

Phosphatidylinositol-3-phosphate

PI(3,5)P2

Phosphatidylinositol-3,5-bisphosphate

PI(5)P

Phosphatidylinositol-5-phosphate

TGN

Trans-golgi network

Notes

Acknowledgments

This work was funded by The South-Eastern Norwegian Regional Health Authority, The Norwegian Cancer Society and The Research Council of Norway, and supported by The Research Council of Norway through its Centers of Excellence funding scheme, project number 179571. We thank Anne Engen, Anne Grethe Myrann and Marianne Smestad for their excellent technical assistance and Tore Skotland for valuable and interesting discussions. We also thank the proteomics core facility, especially Bernd Thiede and Christian Koehler, at the University of Oslo.

Supplementary material

18_2016_2309_MOESM1_ESM.pdf (556 kb)
Supplementary material 1 (PDF 556 kb)

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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Nina Pettersen Hessvik
    • 1
    • 2
  • Anders Øverbye
    • 1
    • 2
  • Andreas Brech
    • 1
    • 2
    • 3
  • Maria Lyngaas Torgersen
    • 1
    • 2
  • Ida Seim Jakobsen
    • 1
    • 2
  • Kirsten Sandvig
    • 1
    • 2
    • 3
  • Alicia Llorente
    • 1
    • 2
    Email author
  1. 1.Department of Molecular Cell Biology, The Norwegian Radium Hospital, Institute for Cancer ResearchOslo University HospitalOsloNorway
  2. 2.Centre for Cancer BiomedicineUniversity of OsloOsloNorway
  3. 3.Department of BiosciencesUniversity of OsloOsloNorway

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