Sorting nexin 17 facilitates LRP recycling in the early endosome
Open accessAbstract
The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multiligand endocytic receptor and a member of the LDL receptor family. Here we show that sorting nexin 17 (Snx 17) is part of the cellular sorting machinery that regulates cell surface levels of LRP by promoting its recycling. While the phox (PX) domain of Snx 17 interacts with phosphatidylinositol-3-phosphate for membrane association, the FERM domain and the carboxyl-terminal region participate in LRP binding. Immunoelectron microscopy shows that the membrane-bound fraction of Snx 17 is localized to the limiting membrane and recycling tubules of early endosomes. The NPxY motif, proximal to the plasma membrane in the LRP cytoplasmic tail, is identified as the Snx 17-binding motif. Functional mutation of this motif did not interfere with LRP endocytosis, but decreased LRP recycling from endosomes, resulting in increased lysosomal degradation. Similar effects are found after knockdown of endogenous Snx 17 expression by short interfering RNA. We conclude that Snx 17 binds to a motif in the LRP tail distinct from the endocytosis signals and promotes LRP sorting to the recycling pathway in the early endosomes.
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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 [31]
The Discussion states that SNX17 recognizes the membrane-proximal NPxY motif in the LRP cytoplasmic tail. The paper also reports that the FERM domain and carboxyl-terminal region participate in LRP binding, rather than attributing binding to the FERM domain alone. The passages found do not establish the claimed recognition of APP or β1 integrins. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSNX17 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 [31]
The Discussion states that SNX17 binds the proximal NPxY motif of LRP, and the Introduction reports a proposed interaction with the LDL receptor’s NPVY motif. Our copy does not establish the claimed APP interaction. The citing sentence assigns β1-integrins to separate citations [33] and [34], not to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSNX17 participates in the recycling of LRP1.
“In addition, SNX17 participates in the recycling of LRP1 - another member of the LDL-R family [31]”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [31]
SNX17 is an adaptor protein localized in the early endosome compartment, mostly due to interaction of its PX domain with early endosomal PI(3)P phospholipids.
“SNX17 is an adaptor protein that is localized in the early endosome compartment [28], [30], [31], mostly due to the interaction of its PX domain with the characteristic early endosomal PI(3)P phospholipids [31], [60].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [31]
SNX17 localizes in the tubular domain of the early endosome, which is related to the recycling pathway.
“Accordingly, it has been shown that SNX17 localizes in the tubular domain of the early endosome, which is related to the recycling pathway [31].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [31]
The region 150-470 of SNX17 is the interacting domain for LRP1 and the scavenger receptor Stabilin1.
“Similarly, it has been shown for LRP1 and the scavenger receptor Stabilin1, that the region of 150–470 of SNX17 is the interacting domain [31], [59].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [31]
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Cited by
Sorted by citations
To degrade or not to degrade: Mechanisms and significance of endocytic recycling
Cullen, P. J., & Steinberg, F. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0053-7 · Cited by 590 · see citing works
Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
McNally, K. E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C. M., Nägele, H., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3610 · Cited by 346 · see citing works
Kanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281 · see citing works
Self-citationLiu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., Han, X., Weeber, E. J., & Bu, G. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4067-10.2010 · Cited by 268 · see citing works
Self-citationThe generation and function of soluble apoE receptors in the CNS
Rebeck, G. W., LaDu, M. J., Estus, S., Bu, G., & Weeber, E. J. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-15 · Cited by 66 · see citing works
Self-citationSorting nexin 17 regulates ApoER2 recycling and reelin signaling
Sotelo, P., Farfán, P., Benitez, M. L., Bu, G., & Marzolo, M.-P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093672 · Cited by 47 · see citing works
Self-citation
- Authors
- van Kerkhof, P., Lee, J., McCormick, L., Tetrault, E., Lu, W., Schoenfish, M., Oorschot, V., Strous, G. J., Klumperman, J., & Bu, G.
- Affiliations
- Washington University in St. Louis (US)
- University Medical Center Utrecht (NL)
- Corresponding author
- Bu, Guojun
- Venue
- The EMBO Journal
- Published
- 2005-07-28
- Volume
- 24
- Issue
- 16
- Pages
- 2851-2861
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1187941
- OpenAlex
- W2158818470
- Cited by
- 148
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 4 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 3 · 2015: 8 · 2014: 10 · 2013: 9 · 2012: 10
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- American Heart Association
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- LDL receptor-related protein, early endosomes, endosomal sorting, NPXY motif, phosphatidylinositol 3-phosphate, PX domain, FERM domain, lysosomal degradation, endocytic receptor
- MeSH terms
- Carrier Proteins, Cell Membrane, Endocytosis, Flow Cytometry, Fluorescence, Glutathione Transferase, Humans, Phosphoric Monoester Hydrolases, Plasmids, Endosomes, Transfection, Microscopy, Immunoelectron, Amino Acid Motifs, Low Density Lipoprotein Receptor-Related Protein-1, Vesicular Transport Proteins, RNA, Small Interfering, Cell Line, Tumor, Immunoprecipitation, Sorting Nexins
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