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Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

McMillan, Kirsty J, Banks, Paul J, Hellel, Francesca LN, Carmichael, Ruth E, Clairfeuille, Thomas, Evans, Ashley J, Heesom, Kate J, Lewis, Philip, Collins, Brett M, Bashir, Zafar I, Henley, Jeremy M, Wilkinson, Kevin A, Cullen, Peter J·2021·eLife
DOI 10.7554/elife.59432PMC PMC8296521

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Abstract

The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

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Crossref · 10.7554/elife.59432

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  • The addition of an N-terminal tag to SNX17 and SNX27 does not interfere with their ability to bind cargo or endosomal membranes.

    “Note that the addition of an N-terminal tag to these proteins does not interfere with their ability to bind cargo or endosomal membranes”

    From PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity (2025) · cites this paper as McMillan et al., 2021

    In Results (‘A neuronal SNX27 interactome’), the paper reports that GFP-SNX27 retained endosomal localisation. The Results figure caption (‘LRFNs interact with SNX27’) also reports an interaction between GFP-SNX27 and LRFN2. These findings support retained activity for tagged SNX27, but the paper does not establish the same for tagged SNX17. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The SNX27-Retromer pathway mediates the retrieval of over 200 transmembrane proteins in neurons, including neurotransmitter receptors, ion channels, and signaling receptors.

    “The better characterized SNX27-Retromer pathway mediates the retrieval of over 200 transmembrane proteins in neurons, including neurotransmitter receptors, ion channels, and signaling receptors”

    From Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity (2025) · cites this paper as McMillan et al., 2021

    The Introduction describes SNX27–retromer-dependent retrieval of internalised integral proteins, and the paper discusses neuronal receptors and ion channels. But the Results section on the neuronal SNX27 interactome identifies 212 SNX27-interacting proteins—not over 200 transmembrane proteins shown to be retrieved. It identifies seven integral proteins within the specified motif-bearing subset. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • SNX27 Retromer-dependent AMPAR recycling is essential for synaptic potentiation and plasticity.

    “SNX27 Retromer-dependent AMPAR recycling is essential for synaptic potentiation and plasticity”

    From Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity (2025) · cites this paper as McMillan et al., 2021

    The Introduction says SNX27 is required to maintain AMPA-receptor-mediated currents during synaptic plasticity. The Results report that LRFN2 suppression attenuated hippocampal long-term potentiation, and the Discussion proposes a role for LRFN2 in SNX27-dependent AMPA receptor recycling. The paper does not establish that retromer-dependent recycling itself is essential for potentiation and plasticity; that wording goes beyond the reported experiments. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane.

    “Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane [26,29,31,58,59].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [59]

    The Introduction (page not provided) describes SNX27’s two interactions and says they enable retrieval of internalized proteins and recycling to the plasma membrane. It does not establish that hundreds of cargoes undergo this process. The Results report 212 SNX27-interacting proteins in cortical neurons, but do not identify all of them as recycling cargoes. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Neuronal SNX27 cargoes include AMPA-type glutamate receptors.

    “Neuronal SNX27 cargoes include key receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type glutamate receptors”

    From PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity (2025) · cites this paper as McMillan et al., 2021

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Metadata

Authors
McMillan, K. J., Banks, P. J., Hellel, F. L., Carmichael, R. E., Clairfeuille, T., Evans, A. J., Heesom, K. J., Lewis, P., Collins, B. M., Bashir, Z. I., Henley, J. M., Wilkinson, K. A., & Cullen, P. J.
Affiliations
  • School of Biochemistry, University of Bristol, Bristol, United Kingdom
  • School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
  • Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia
  • Proteomics facility, School of Biochemistry, University of Bristol, Bristol, United Kingdom
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-07-12
Volume
10
ISSN
2050-084X
DOI
10.7554/elife.59432
PMC
PMC8296521
Cited by
21
References
7
Language
en
Licence
Funders
  • Medical Research Council (MR/L007363/1, MR/P018807/1)
  • Wellcome Trust (104568/Z/14/2, 220260/Z/20/Z)
  • Lister Institute of Preventive Medicine
  • National Health and Medical Research Council (APP1136021, APP1099114)
  • Biotechnology and Biological Sciences Research Council (BB/R00787X/1)
  • Royal Society (RSRP\R1\211004)

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