SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways
Open accessAbstract
The FERM-like domain–containing sorting nexins of the SNX17/SNX27/SNX31 family have been proposed to mediate retrieval of transmembrane proteins from the lysosomal pathway. In this paper, we describe a stable isotope labeling with amino acids in culture–based quantitative proteomic approach that allows an unbiased, global identification of transmembrane cargoes that are rescued from lysosomal degradation by SNX17. This screen revealed that several integrins required SNX17 for their stability, as depletion of SNX17 led to a loss of β1 and β5 integrins and associated a subunits from HeLa cells as a result of increased lysosomal degradation. SNX17 bound to the membrane distal NPXY motif in β integrin cytoplasmic tails, thereby preventing lysosomal degradation of β integrins and their associated a subunits. Furthermore, SNX17-dependent retrieval of integrins did not depend on the retromer complex. Consistent with an effect on integrin recycling, depletion of SNX17 also caused alterations in cell migration. Our data provide mechanistic insight into the retrieval of internalized integrins from the lysosomal degradation pathway, a prerequisite for subsequent recycling of these matrix receptors.
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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 [34]
The Results and discussion (Fig. 4 F–H; page unavailable) show that SNX17’s FERM-like domain binds the membrane-distal NPXY motif in the β1-integrin cytoplasmic tail. The paper mentions SNX17 in connection with APP trafficking and cites earlier work on its cargo binding, but our copy does not state that this domain recognizes NPXY motifs in APP or LRP1 cytoplasmic tails. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSNX17 mediates the recycling and degradation of β1-integrins.
“and mediates the recycling and degradation of β1-integrins [33], [34].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [34]
SNX17 avoids integrin lysosomal degradation and aids in more efficient recycling from the EEA1/Rab4-positive compartment by binding to the distal NPxY motif of the β1 subunit.
“It is worth mentioning here that in contrast to the role in ApoER2 trafficking, SNX17 accomplishes a different role in the trafficking and degradation of integrin α5β1; by binding to the distal NPxY motif of the β1 subunit, SNX17 avoids integrin lysosomal degradation and aids in a more efficient recycling from the EEA1/Rab4-positive compartment.”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [34]
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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
Self-citationRetriever 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
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
- Authors
- Steinberg, F., Heesom, K. J., Bass, M. D., & Cullen, P. J.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Cullen, Peter J.
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2012-04-09
- Volume
- 197
- Issue
- 2
- Pages
- 219-230
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3328392
- OpenAlex
- W2123105928
- Cited by
- 206
- References
- 1
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 14 · 2023: 9 · 2022: 19 · 2021: 12 · 2020: 12 · 2019: 18 · 2018: 18 · 2017: 13 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 27 · 2012: 6
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- Wellcome Trust (088419, 089928/Z/09/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- SNX17, sorting nexins, integrins, lysosomal degradation, protein retrieval, recycling pathway, NPXY motif, retromer complex, cell migration, HeLa cells
- MeSH terms
- Biological Transport, Active, Cell Movement, HeLa Cells, Humans, Lysosomes, Integrin beta1, Protein Transport, Vesicular Transport Proteins, RNA Interference, RNA, Small Interfering, Integrin beta Chains, Proteomics, Cell Line, Tumor, HEK293 Cells, Sorting Nexins
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