A lysosome–plasma membrane–sphingolipid axis linking lysosomal storage to cell growth arrest

Maura Samarani, Nicoletta Loberto, Giulia Soldà, Letizia Straniero, Rosanna Asselta, Stefano Duga, Giulia Lunghi, Fabio A. Zucca, Laura Mauri, Maria Grazia Ciampa, Domitilla Schiumarini, Rosaria Bassi, Paola Giussani, Elena Chiricozzi, Alessandro Prinetti, Massimo Aureli, Sandro Sonnino

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids (i.e., sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp-1 on the PM of sucrose-loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose-loaded fibroblasts. The inhibition of b-glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment.

Original languageEnglish
Pages (from-to)5685-5702
Number of pages18
JournalFASEB Journal
Volume32
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

Fingerprint

Cell growth
Cell membranes
Fibroblasts
Cell Membrane
Sucrose
Glucosylceramidase
Growth
Glycosphingolipids
Ceramides
Cell proliferation
Cells
Lysosome-Associated Membrane Glycoproteins
G(M3) Ganglioside
Cell Proliferation
Neurodegenerative diseases
Glucosylceramides
Lysosomal Storage Diseases
Cathepsin D
Intracellular Membranes
Sphingolipids

Keywords

  • Catabolism
  • Cell proliferation
  • Cell surface
  • Glycohydrolases
  • Glycosphingolipids

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

A lysosome–plasma membrane–sphingolipid axis linking lysosomal storage to cell growth arrest. / Samarani, Maura; Loberto, Nicoletta; Soldà, Giulia; Straniero, Letizia; Asselta, Rosanna; Duga, Stefano; Lunghi, Giulia; Zucca, Fabio A.; Mauri, Laura; Ciampa, Maria Grazia; Schiumarini, Domitilla; Bassi, Rosaria; Giussani, Paola; Chiricozzi, Elena; Prinetti, Alessandro; Aureli, Massimo; Sonnino, Sandro.

In: FASEB Journal, Vol. 32, No. 10, 01.10.2018, p. 5685-5702.

Research output: Contribution to journalArticle

Samarani, M, Loberto, N, Soldà, G, Straniero, L, Asselta, R, Duga, S, Lunghi, G, Zucca, FA, Mauri, L, Ciampa, MG, Schiumarini, D, Bassi, R, Giussani, P, Chiricozzi, E, Prinetti, A, Aureli, M & Sonnino, S 2018, 'A lysosome–plasma membrane–sphingolipid axis linking lysosomal storage to cell growth arrest', FASEB Journal, vol. 32, no. 10, pp. 5685-5702. https://doi.org/10.1096/fj.201701512RR
Samarani, Maura ; Loberto, Nicoletta ; Soldà, Giulia ; Straniero, Letizia ; Asselta, Rosanna ; Duga, Stefano ; Lunghi, Giulia ; Zucca, Fabio A. ; Mauri, Laura ; Ciampa, Maria Grazia ; Schiumarini, Domitilla ; Bassi, Rosaria ; Giussani, Paola ; Chiricozzi, Elena ; Prinetti, Alessandro ; Aureli, Massimo ; Sonnino, Sandro. / A lysosome–plasma membrane–sphingolipid axis linking lysosomal storage to cell growth arrest. In: FASEB Journal. 2018 ; Vol. 32, No. 10. pp. 5685-5702.
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