Adaptor Protein Sorting Nexin 17 Regulates Amyloid Precursor Protein Trafficking and Processing in the Early Endosomes
Open accessAbstract
Accumulation of extracellular amyloid beta peptide (Abeta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of Abeta from APP is greatly affected by the subcellular localization and trafficking of APP. Here we have identified a novel intracellular adaptor protein, sorting nexin 17 (SNX17), that binds specifically to the APP cytoplasmic domain via the YXNPXY motif that has been shown previously to bind several cell surface adaptors, including Fe65 and X11. Overexpression of a dominant-negative mutant of SNX17 and RNA interference knockdown of endogenous SNX17 expression both reduced steady-state levels of APP with a concomitant increase in Abeta production. RNA interference knockdown of SNX17 also decreased APP half-life, which led to the decreased steady-state levels of APP. Immunofluorescence staining confirmed a colocalization of SNX17 and APP in the early endosomes. We also showed that a cell surface adaptor protein, Dab2, binds to the same YXNPXY motif and regulates APP endocytosis at the cell surface. Our results thus provide strong evidence that both cell surface and intracellular adaptor proteins regulate APP endocytic trafficking and processing to Abeta. The identification of SNX17 as a novel APP intracellular adaptor protein highly expressed in neurons should facilitate the understanding of the relationship between APP intracellular traffic…
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By using pooled CRISPR-Cas9 targeted screening, we discovered genes for which variants cause autosomal dominant forms of neurodegeneration (SLC33A1, SNX17, GRN, VPS35, CLN3, NPC2) as genetic modulators of lipid droplet formation in microglia.
“By using pooled CRISPR-Cas9 targeted screening, we discovered genes for which variants cause autosomal dominant forms of neurodegeneration (SLC33A1, SNX17, GRN, VPS35, CLN3, NPC2) as genetic modulators of lipid droplet formation in microglia32–35.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [33]
SNX17, specifically through its FERM domain, recognizes an NPxY motif in the cytoplasmic domains of LRP1, APP and β1 integrins.
“SNX17, specifically through its FERM domain, recognizes an NPxY motif in the cytoplasmic domains of LRP1, APP and β1 integrins [31], [32], [34], [35].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [32]
SNX17 regulates the cell surface levels and half-life of APP.
“regulates the cell surface levels and half-life of APP [32]”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [32]
The interaction of APP with SNX17 regulates its processing.
“Additionally it has been shown that the interaction of APP with SNX17 regulates its processing [32].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [32]
SNX17 silencing decreases the surface levels of APP, which is associated with deficient recycling.
“It has also been shown that SNX17 silencing decreases the surface levels of APP, which is associated with deficient recycling [32].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [32]
SNX17 interacts with the NPxY motif of LRP1, LDL-R, APP, and β1-integrins.
“This falls in agreement with previous reports showing the interaction of SNX17 with the NPxY motif of LRP1, LDL-R, APP [28], [31], [32], and recently with β1-integrins [33], [34].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [32]
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Sorting nexin 17 regulates ApoER2 recycling and reelin signaling
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- Authors
- Lee, J., Retamal, C., Cuitiño, L., Caruano-Yzermans, A., Shin, J.-E., van Kerkhof, P., Marzolo, M.-P., & Bu, G.
- Affiliations
- Washington University in St. Louis (US)
- Pontificia Universidad Católica de Chile (CL)
- Corresponding author
- Bu, Guojun
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 283
- Issue
- 17
- Pages
- 11501-11508
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2431074
- OpenAlex
- W2153266207
- Cited by
- 162
- References
- 3
- Citations by year
- 2025: 9 · 2024: 7 · 2023: 8 · 2022: 8 · 2021: 4 · 2020: 13 · 2019: 9 · 2018: 14 · 2017: 14 · 2016: 7 · 2015: 8 · 2014: 10 · 2013: 13 · 2012: 10
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute on Aging (R01AG027924)
- Fogarty International Center (TW006456, R03TW006456)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, amyloid-beta, early endosomes, APP trafficking, adaptor proteins, Dab2, APP endocytosis, APP processing, Alzheimer's disease
- MeSH terms
- Animals, Cell Membrane, Cytoplasm, Endocytosis, Gene Expression Regulation, Humans, Models, Biological, Neurons, Endosomes, Amyloid beta-Peptides, Protein Structure, Tertiary, Protein Transport, Vesicular Transport Proteins, Cell Line, Tumor, Mice, Sorting Nexins
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