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Cited by 13Cellular transport and secretionLysosomal Storage Disorders ResearchNeurogenesis and neuroplasticity mechanisms

Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

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Salgado-Polo, Fernando, van Veen, Michiel, van den Broek, Bram, Jalink, Kees, Leyton-Puig, Daniela, Perrakis, Anastassis, Moolenaar, Wouter H., Matas-Rico, Elisa·2020·Journal of Cell Science
DOI 10.1242/jcs.235044PMC PMC7033719

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Abstract

GDE2 (also known as GDPD5) is a multispanning membrane phosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby promotes neuronal differentiation both in vitro and in vivo. GDE2 is a prognostic marker in neuroblastoma, while loss of GDE2 leads to progressive neurodegeneration in mice; however, its regulation remains unclear. Here, we report that, in immature neuronal cells, GDE2 undergoes constitutive endocytosis and travels back along both fast and slow recycling routes. GDE2 trafficking is directed by C-terminal tail sequences that determine the ability of GDE2 to cleave GPI-anchored glypican-6 (GPC6) and induce a neuronal differentiation program. Specifically, we define a GDE2 truncation mutant that shows aberrant recycling and is dysfunctional, whereas a consecutive deletion results in cell-surface retention and gain of GDE2 function, thus uncovering distinctive regulatory sequences. Moreover, we identify a C-terminal leucine residue in a unique motif that is essential for GDE2 internalization. These findings establish a mechanistic link between GDE2 neuronal function and sequence-dependent trafficking, a crucial process gone awry in neurodegenerative diseases. This article has an associated First Person interview with the first author of the paper.

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Authors
Salgado-Polo, F., van Veen, M., van den Broek, B., Jalink, K., Leyton-Puig, D., Perrakis, A., Moolenaar, W. H., & Matas-Rico, E.
Affiliations
  • The Netherlands Cancer Institute (NL)
  • The Netherlands Cancer Institute 2 Division of Cell Biology , , Plesmanlaan 121, 1066 CX Amsterdam , The Netherlands
  • The Netherlands Cancer Institute 1 Division of Biochemistry, Oncode Institute , , Plesmanlaan 121, 1066 CX Amsterdam , The Netherlands
Corresponding author
  • Moolenaar, Wouter H.
  • Matas-Rico, Elisa
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2020-02-01
Volume
133
Issue
3
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.235044
PMC
PMC7033719
OpenAlex
W2999422078
Cited by
13
References
1
Citations by year
2025: 1 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3
FWCI
1.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cell Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
Funders
KWF Kankerbestrijding (2017-10215)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
phospholipase D, GPI-anchored proteins, neuronal differentiation, protein trafficking, endocytosis, recycling pathway, C-terminal tail, neurodegeneration, neuroblastoma
MeSH terms
Animals, Cell Differentiation, Neuroblastoma, Phosphoric Diester Hydrolases, Phospholipases, Glycosylphosphatidylinositols, Mice

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