The PX‐domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor
Open accessAbstract
Sorting nexins (SNXs) comprise a family of proteins characterized by the presence of a phox-homology domain, which mediates the association of these proteins with phosphoinositides and recruits them to specific membranes or vesicular structures within cells. Although only limited information about SNXs and their functions is available, they seem to be involved in membrane trafficking and sorting processes by directly binding to target proteins such as certain growth factor receptors. We show that SNX17 binds to the intracellular domain of some members of the low-density lipoprotein receptor (LDLR) family such as LDLR, VLDLR, ApoER2 and LDLR-related protein. SNX17 resides on distinct vesicular structures partially overlapping with endosomal compartments characterized by the presence of EEA1 and rab4. Using rhodamine-labeled LDL, it was possible to demonstrate that during endocytosis, LDL passes through SNX17-positive compartments. Functional studies on the LDLR pathway showed that SNX17 enhances the endocytosis rate of this receptor. Our results identify SNX17 as a novel adaptor protein for LDLR family members and define a novel mechanism for modulation of their endocytic activity.
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The SNX17 PX domain facilitates interaction between SNX17 and PI3P-enriched membranes, particularly early endosome membranes that are positive for EEA1.
“Its PX domain facilitates the interaction between SNX17 and PI3P-enriched membranes, particularly with the early endosome membranes that are positive for EEA1 [27]–[29].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
The Introduction says that PX domains mediate PI(3)P interactions for at least some sorting nexins, but does not establish that SNX17’s PX domain binds PI3P. The Results show that SNX17 partially colocalizes with EEA1-positive early endosomal compartments, not that PI3P binding causes its localization there. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSNX17 overexpression increases the number of endocytic cycles of LDL-R, implying an increase in recycling efficiency.
“In the case of LDL-R, SNX17 overexpression increases the number of endocytic cycles, implying an increase in recycling efficiency [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
The Results report that SNX17-expressing cells had an approximately twofold higher internalization index, defined as the number of times each LDL receptor cycles during a given interval. The Discussion suggests faster movement through the early endocytic compartment and/or recycling compartments; it does not establish that recycling efficiency specifically increased. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredStockinger et al identified SNX17 as an interacting protein using the ApoER2 tail as bait.
“In the case of ApoER2, the studies by Stockinger et al that utilized a yeast two-hybrid screen, and identified SNX17 as an interacting protein using ApoER2 tail as bait [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
SNX17 is present in the fraction containing early endosomal membranes.
“In agreement with previous reports, SNX17 was present in the fraction containing early endosomal membranes. [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
Full-length SNX17 interacts with ApoER2.
“As was previously reported, we observed that full-length SNX17 interacts with ApoER2 [27];”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
Stockinger et al discarded the NPxY motif as a SNX17 binding motif for receptors including ApoER2, in part because megalin/LRP2 has three NPxY motifs but did not bind SNX17.
“However, in contrast, the authors discarded the NPxY motif as a SNX17 binding motif for the receptors - including ApoER2 - in part because megalin/LRP2, another receptor of the LDL-R family, has three NPxY motifs but did not bind SNX17 [27], [37].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
SNX17 increases the number of endocytic cycles performed by the LDL-R.
“SNX17 also increases the number of endocytic cycles performed by the LDL-R [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
A yeast two-hybrid screen showed that SNX17 interacts with P-selectin and LDL-R family proteins.
“A yeast two-hybrid screen showed that SNX17 interacts with P-selectin [26] and LDL-R family proteins [26], [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
VLDLR is able to interact with SNX17, as determined by GST pull-down.
“Because VLDLR is also able to interact with SNX17 [27] as determined by GST pull-down, we cannot rule out a possible effect of SNX17 knockdown in VLDLR trafficking and signaling.”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
SNX17 knockdown did not affect the recycling of megalin/LRP2.
“The role of SNX17 in ApoER2 recycling is dependent on the specific interaction with the receptor and is not caused by a general effect on the endosomal compartment because SNX17 knockdown did not affect the recycling of megalin/LRP2 [27].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [27]
The Discussion reports that SNX17 does not bind megalin, but it does not report megalin recycling after SNX17 knockdown. The Results describe SNX17 expression experiments measuring LDLR endocytosis, not a knockdown experiment measuring megalin recycling (searched: SNX17 knockdown, megalin recycling, siRNA and depletion). (LLM, conf=0.78)
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Cites
Haft, C. R., de la Luz Sierra, M., Barr, V. A., Haft, D. H., & Taylor, S. I. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7278 · Cited by 244 · see citing works
The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2
Stockinger, W., Brandes, C., Fasching, D., Hermann, M., Gotthardt, M., Herz, J., Schneider, W. J., & Nimpf, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004119200 · Cited by 239 · see citing works
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- Zhong,Q., Lazar,C.S., Tronchere,H., Sato,T., Meerloo,T., Yeo,M., Songyang,Z., Emr,S. and Gill,G.N. (2002) Endosomal localization and function of sorting nexin 1. Proc. Natl Acad. Sci. USA , 99 , 6767-6772.
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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
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Xie, Y., Zhang, X., Xu, P., Zhao, N., Zhao, Y., Li, Y., Hong, Y., Peng, M., Yuan, K., Wan, T., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci128114 · Cited by 57 · see citing works
Sorting 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
- Authors
- Stockinger, W., Sailler, B., Strasser, V., Recheis, B., Fasching, D., Kahr, L., Schneider, W. J., & Nimpf, J.
- Affiliations
- University of Vienna (AT)
- Corresponding author
- Nimpf, Johannes
- Venue
- The EMBO Journal
- Published
- 2002-08-15
- Volume
- 21
- Issue
- 16
- Pages
- 4259-4267
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126172
- OpenAlex
- W1983416390
- Cited by
- 130
- References
- 2
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 7 · 2012: 7
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- SNX17, sorting nexins, LDL receptor, VLDLR, ApoER2, LDL receptor family, endocytosis, adaptor proteins, phox homology domain, EEA1, Rab4, endosomes, membrane trafficking, phosphoinositides
- MeSH terms
- Animals, Carrier Proteins, Cell Line, Endocytosis, Fluorescent Antibody Technique, Nerve Tissue Proteins, Receptors, LDL, Recombinant Proteins, Receptors, Lipoprotein, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Vesicular Transport Proteins, Mice, Sorting Nexins
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