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Cited by 36Cellular transport and secretionAutophagy in Disease and TherapyReceptor Mechanisms and Signaling

The DOI matches its Crossref record; 196 of the 196 references it cites were found in a registry or an index; none of the 216 sources its claims cite is checked for support yet.

Receptor Recycling by Retromer

Open access
Carosi, Julian M., Denton, Donna, Kumar, Sharad, Sargeant, Timothy J.·2023·Molecular and Cellular Biology
DOI 10.1080/10985549.2023.2222053PMC PMC10348044
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Abstract

The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse metabolic programs. More than 20 years ago, retromer was discovered as an essential regulator of endosome-to-Golgi transport in yeast; since then, significant progress has been made to characterize how metazoan retromer components assemble to enable its engagement with endosomal membranes, where it sorts cargo receptors from endosomes to the trans-Golgi network or plasma membrane through recognition of sorting motifs in their cytoplasmic tails. In this review, we examine retromer regulation by exploring its assembled structure with an emphasis on how a range of adaptor proteins shape the process of receptor trafficking. Specifically, we focus on how retromer is recruited to endosomes, selects cargoes, and generates tubulovesicular carriers that deliver cargoes to target membranes. We also examine how cells adapt to distinct metabolic states by coordinating retromer expression and function. We contrast similarities and differences between retromer and its related complexes: retriever and commander/CCC, as well as their interplay in receptor trafficking. We elucidate how loss of retromer regulation is central to the pathology of various neurogenerative and metabolic diseases, as well as microbial infections, and highlight both opportunities and cautions for therapeutics that target retromer. Finally, with a focus on understanding the mechanisms that govern retromer regulation, we outline new directions for the field moving forward.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes two decades of work on the retromer complex, describing how it assembles with itinerariespecific adaptors (SNX-BAR, SNX3, SNX27) to sort receptors from endosomes to the trans-Golgi network or plasma membrane. It also contrasts retromer with the related retriever and commander/CCC complexes and surveys its roles in neurodegeneration, metabolic disease, and microbial infection.

Key findings

  • Retromer is a conserved VPS35–VPS26–VPS29 assembly that sorts cargo receptors (e.g., CI-MPR, sortilin, DMT1-II, GLUT1, β2 adrenergic receptor) away from lysosomal degradation; VPS26A and VPS26B form mutually exclusive complexes with distinct endosomal localization and cargo specificity (e.g., VPS26A traffics CI-MPR, VPS26B does not).
  • Three main adaptor-defined itineraries are described: SNX-BAR-retromer and SNX3-retromer for endosome-to-Golgi retrieval (tubular and vesicular carriers, respectively), and SNX27-retromer for endosome-to-plasma membrane recycling.
  • The VPS35 D620N mutation causes autosomal dominant Parkinson's disease by impairing the VPS35–FAM21 interaction and WASH complex recruitment, perturbing endosome-to-Golgi (but not plasma membrane) itineraries and impairing ATG9A trafficking and autophagosome formation.
  • Retromer is hijacked by pathogens: the *Legionella* effector RidL outcompetes TBC1D5/VARP for VPS29 binding, and a CRISPR screen identified retromer components (VPS35, VPS26A, VPS29), SNX27, and commander/CCC members as host factors required for SARS-CoV-2 infection.

Methods

  • Narrative review; the authors state that no new data were created or analyzed ("Data sharing is not applicable to this article as no new data were created or analyzed in this study").
  • Synthesizes structural, biochemical, genetic, and cell-biological literature on retromer assembly, adaptor interactions, post-translational modifications (summarized in Table 1), and disease associations.
  • Includes a comparative treatment of the related retriever (VPS26C–VPS35L–VPS29) and commander/CCC complexes.

Limitations

  • The authors state that upstream regulation of retromer—how cells fine-tune its function in response to nutrient availability, growth factor stimulation, and metabolic state switching—is "only beginning to be explored."
  • The text makes evident unresolved contradictions in the field: recent work reporting that retromer is dispensable for CI-MPR trafficking (with SNX-BARs acting independently) is described as "difficult to square with previous findings" and as calling into question current understanding of SNX-BAR-retromer.
  • The text notes "considerable variation in the reported retromer structures," which may reflect diverse conformations or technical differences in approaches (e.g., the arch-like architecture may have been influenced by the Vps5 homodimer on Folch lipid liposomes).
  • Conflicting findings on amyotrophic lateral sclerosis are noted: enhancing retromer stability improved outcomes in Sod1^G93A mice, whereas others reported that enforcing Vps35 expression enhances paralysis, leaving it "unclear if targeting retromer will be useful" there.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/10985549.2023.2222053

Cites

196 of 196 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 216 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Endosome-to-plasma membrane recycling is mediated by a complex of retromer with SNX27 (SNX27-retromer) that generates tubular endosomal carriers.

    “In contrast, endosome-to-plasma membrane recycling is mediated by a complex of retromer with SNX27 (SNX27-retromer) that generates tubular endosomal carriers (Fig. 1A).17,45”
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  • Premisecitation

    Retromer is organized into dimer complexes (dimers of VPS29-VPS35-VPS26 trimers) with arch-like architecture.

    “Retromer is organized into dimer complexes (i.e., dimers of VPS29-VPS35-VPS26 trimers) with arch-like architecture.”
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  • Premisecitation

    The PX domains of SNX1/2 show a strong preference for binding to phosphatidylinositol (PtdIns)(3,4)P2 on membranes.

    “The PX domains of SNX1/2 show a strong preference for binding to phosphatidylinositol (PtdIns)(3,4)P 2 on membranes.53”
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  • Premisecitation

    In metazoan species, retromer also regulates endosome-to-plasma membrane trafficking.

    “Apart from this, in metazoan species retromer also regulates endosome-to-plasma membrane trafficking (Fig. 1A).16,17”
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  • Interpretationcitation

    VPS29 is catalytically inactive.

    “In agreement with this, it was subsequently found that VPS29 does not display metallophosphoesterase activity against generic substrates in vitro.29,36”
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    Premisecitation

    Retromer depletion impairs endosome-to-Golgi trafficking of the CI-MPR and enhances secretion of the lysosomal hydrolase cathepsin D, thus reducing the degradative capacity of lysosomes.

    “Similarly, retromer depletion impairs endosome-to-Golgi trafficking of the CI-MPR and enhances secretion of the lysosomal hydrolase cathepsin D, thus reducing the degradative capacity of lysosomes.15,16,46”
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    Premisecitation

    Retromer also appears to organize into tetramers, flat chains, and a monomeric complex.

    “Retromer also appears to organize into tetramers (i.e., tetramers of VPS29-VPS35-VPS26 trimers), flat chains, as well as a monomeric complex (i.e., a monomer of VPS29-VPS35-VPS26 trimer).39,40”
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    Premisecitation

    VPS26 and VPS29 bind independently to the N- and C-terminal regions of VPS35, respectively; each component is necessary to enable maximal stability of the others.

    “VPS26 and VPS29 bind independently to the N-and C-terminal regions of VPS35, respectively, however, each component is necessary to enable maximal stability of the others.32,35”
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    Premisecitation

    SNX5/6 do not appear to bind to phospholipid membranes, and likely are recruited to endosomes by binding to the cytoplasmic tails of receptor cargoes.

    “In contrast, SNX5/6 do not exhibit appear to bind to phospholipid membranes, and likely are recruited to endosomes by binding to the cytoplasmic tails of receptor cargoes.44,53,54”
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    Premisecitation

    Retromer forms higher order functional complexes by associating with SNX1/2 and SNX5/6 (SNX-BAR-retromer) or with SNX3 (SNX3-retromer) to regulate endosome-to-Golgi retrieval pathways via tubular or vesicular endosomal carriers, respectively.

    “By and large, retromer forms higher order functional complexes by associating with SNX1/2 and SNX5/6 (SNX-BAR-retromer) or with SNX3 (SNX3-retromer) to regulate endosome-to-Golgi retrieval pathways via tubular or vesicular endosomal carriers, respectively (Fig. 1A and B).[41][42][43][44]”
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  • It may state two separate claims as one.

    Premisecitation

    Metazoan retromer functionally associates with SNX1/2 and SNX5/6, but these interactions appear to be somewhat transient or of low affinity.

    “Although metazoan retromer functionally associates with SNX1/2 and SNX5/6, these interactions appear to be somewhat transient or of low affinity, as these components do not consistently co-immunoprecipitate together.15,21,26,48,49”
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  • It may state two separate claims as one.

    Premisecitation

    VPS26 exists as two paralogues (VPS26A and B) that compete for binding to VPS35, forming mutually exclusive retromer complexes.

    “VPS26 exists as two paralogues (VPS26A and B) that compete for binding to VPS35, forming mutually exclusive retromer complexes.26,27”
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    Premisecitation

    VPS26A binds to and traffics the CI-MPR, whereas VPS26B does not.

    “for example, VPS26A binds to and traffics the CI-MPR, whereas VPS26B does not.26”
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  • It may state two separate claims as one.

    Premisecitation

    Retromer is a highly conserved assembly of VPS35, VPS26, and VPS29 that was discovered as a regulator of endosome-to-Golgi receptor trafficking in Saccharomyces cerevisiae.

    “Retromer is a highly conserved assembly of VPS35, VPS26, and VPS29 that was discovered as a regulator of endosome-to-Golgi receptor trafficking in Saccharomyces cerevisiae (Fig. 1A).2,22”
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    SNX-BAR-retromer was first identified in S. cerevisiae, where the retromer trimer stably interacts with Vps5 and Vps17.

    “SNX-BAR-retromer was first identified in S. cerevisiae, where the retromer trimer stably interacts with Vps5 and Vps17 (SNX1/2 and SNX5/6 orthologs, respectively).2,22,47”
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    • cites [47]

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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Considerable variation in reported retromer structures reflects diverse conformations and assemblies which may exist in eukaryotes or may arise from technical differences in the approaches used.

    “It is important to note considerable variation in the reported retromer structures.[38][39][40] These reflect diverse conformations and assemblies which may exist in eukaryotes or may arise from technical differences in the approaches used.”
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  • It may state two separate claims as one.

    Premisecitation

    VPS26 contains an arrestin fold and has a mobile loop within its C-terminus (amino acids 235-246) that binds to the N-terminus of VPS35.

    “Structurally, VPS26 contains an arrestin fold and has a mobile loop within its Cterminus (amino acids 235-246) that binds to the N-terminus of VPS35.24,25”
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  • It may state two separate claims as one.

    Premisecitation

    Depletion of either SNX1, -5 or -6 leads to CI-MPR mis-trafficking; SNX2 depletion does not, suggesting that its loss may be functionally compensated for by SNX1.

    “Depletion of either SNX1, -5 or -6 leads to CI-MPR mis-trafficking; strikingly, SNX2 depletion does not, suggesting that its loss may be functionally compensated for by SNX1.44,51,52”
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  • It may state two separate claims as one.

    Premisecitation

    Retriever is a stable trimer consisting of VPS26C, VPS35L, and VPS29 with predicted similarity in overall architecture to retromer.

    “Retriever is a stable trimer consisting of VPS26C, VPS35L, and VPS29 with predicted similarity in overall architecture to retromer.20”
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    Premisecitation

    The retromer-TBC1D5 complex activates mTORC1 signaling and thus suppresses autophagy by restricting Rab7 hyperactivation.

    “The retromer-TBC1D5 complex activates mTORC1 signaling and thus suppresses autophagy by restricting Rab7 hyperactivation.118”
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  • It may state two separate claims as one.

    Premisecitation

    VPS26C and VPS35L share predicted structural homology to VPS26 and VPS35, respectively.

    “VPS26C and VPS35L share predicted structural homology to VPS26 and VPS35, respectively. 20,131”
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    Premisecitation

    Phosphorylation of TFEB S211 by mTORC1 antagonizes its entry into the nucleus and inhibits transcription of its target genes.

    “Phosphorylation of TFEB S211 by mTORC1 antagonizes its entry into the nucleus and inhibits transcription of its target genes.129”
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  • It may state two separate claims as one.

    Premisecitation

    The VPS35 D620N mutation reduces the endosomal recruitment of the WASH complex and perturbs the endosome-to-Golgi itineraries but not the plasma membrane ones.

    “This mutation reduces the endosomal recruitment of the WASH complex and perturbs the endosome-to-Golgi itineraries but not the plasma membrane ones. 54,95”
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    Premisecitation

    TBC1D5 contains a TBC/GTPase-activating protein (GAP) domain that catalyzes the GTP-to-GDP hydrolysis of Rab7 in vitro, a catalytic function that is enhanced when it is bound to retromer.

    “TBC1D5 contains a TBC/GTPase-activating protein (GAP) domain that catalyzes the GTP-to-GDP hydrolysis of Rab7 in vitro, a catalytic function that is enhanced when it is bound to retromer.107,109”
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  • It may state two separate claims as one.

    Premisecitation

    VARP interacts with retromer and regulates the endosome-to-plasma membrane trafficking itineraries of some but not all cargoes.

    “VARP interacts with retromer and regulates the endosome-to-plasma membrane trafficking itineraries of some but not all cargoes.120”
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  • It may state two separate claims as one.

    Premisecitation

    Retromer recruits the WASH complex to endosomes which, together, form a supercomplex via VPS35 binding to the unstructured tail of FAM21.

    “Retromer recruits the WASH complex to endosomes which, together, form a supercomplex via VPS35 binding to the unstructured tail of FAM21.[87][88][89]”
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  • It may state two separate claims as one.

    Premisecitation

    The WASH complex nucleates branched chains of F-actin on the endosomal surface and coordinates endosomal tubule scission/fission.

    “The Wiskott-Aldrich syndrome and scar homologue (WASH) complex nucleates branched chains of F-actin on the endosomal surface and coordinates endosomal tubule scission/fission.[84][85][86]”
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    Premisecitation

    The Mon1-Ccz1-C18orf8 complex is a guanine nucleotide exchange factor that switches Rab7 from a GDP- to GTP-bound state, an upstream requirement for the recruitment of retromer to the endosomal surface.

    “The Mon1-Ccz1-C18orf8 complex is a guanine nucleotide exchange factor that switches Rab7 from a GDP-to GTP-bound state, an upstream requirement for the recruitment of retromer to the endosomal surface.[101][102][103][104]”
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  • It may state two separate claims as one.

    Premisecitation

    SNX27 lacks a BAR domain, akin to SNX3, but SNX27-retromer interacts with SNX1, -2, and -5 which mediate tubular carrier formation for the endosome-to-plasma membrane trafficking pathway.

    “SNX27 lacks a BAR domain, akin to SNX3, but a key difference between the two is that SNX27-retromer interacts with SNX1, -2, and -5 which mediate tubular carrier formation for the endosome-to-plasma membrane trafficking pathway.17”
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  • It may state two separate claims as one.

    Premisecitation

    Similar to retromer, retriever controls the steady-state abundance of >120 cell surface proteins as well as copper and low-density lipoprotein homeostasis.

    “Similar to retromer, retriever controls the steady-state abundance of >120 cell surface proteins as well as copper and low-density lipoprotein homeostasis.20,132,135”
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  • It may state two separate claims as one.

    Premisecitation

    Cells lacking VPS35 or VPS29 display reduced mTORC1 signalling and increased nuclear localization of TFEB.

    “cells lacking VPS35 or VPS29 display reduced mTORC1 signalling and increased nuclear localization of TFEB”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • It may state two separate claims as one.

    Premisecitation

    The VPS35 D620N mutation causes autosomal dominant Parkinson's disease and impairs the VPS35-FAM21 interaction.

    “Importantly, the VPS35 D620N mutation causes autosomal dominant Parkinson's disease and impairs the VPS35-FAM21 interaction.54,95”
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    Premisecitation

    Following insulin stimulation, VPS35 attachment to endomembranes is modestly reduced; this is abolished by expression of a phosphodeficient mutant of VPS35 S7A.

    “Following insulin stimulation, VPS35 attachment to endomembranes is modestly reduced; however, this is abolished by the expression of a phosphodeficient mutant of VPS35 S7A.122”
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    Premisecitation

    Depletion of WASH, strumpellin or KIAA1033 leads to uncontrolled endosome tubulation and CI-MPR mis-trafficking, indicating that endosomal F-actin polymerization is a prerequisite for scission.

    “Depletion of WASH, strumpellin or KIAA1033 leads to uncontrolled endosome tubulation and CI-MPR mis-trafficking, indicating that endosomal F-actin polymerization is a prerequisite for scission.87,90”
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  • It may state two separate claims as one.

    Premisecitation

    Depletion of CCDC93, COMMD3 or VPS26C elevates PtdIns(3)P levels and impairs the plasma membrane trafficking of integrin a5.

    “Depletion of CCDC93, COMMD3 or VPS26C elevates PtdIns(3)P levels and impairs the plasma membrane trafficking of integrin a5”
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    Premisecitation

    Similar to SNX27, SNX17 has PX and FERM domains that dock onto PtdIns(3)P and participate in selection of NPxY/NxxY sorting motifs.

    “Similar to SNX27, SNX17 has PX and FERM domains that dock onto PtdIns(3)P and participate in selection of NPxY/NxxY sorting motifs, respectively (where x is any amino acid).53,80”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [80]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    A phosphomimetic mutant of VPS26B S302/304D displays impaired binding to SNX27, yet increased delivery of its cargo GLUT1 to the plasma membrane.

    “A phosphomimetic mutant of VPS26B S302/304D displays impaired binding to SNX27, yet increased delivery of its cargo GLUT1 to the plasma membrane.124”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    SNX3 can recruit retromer onto the endosomal surface, and from here SNX3-retromer regulates the endosome-to-Golgi trafficking of its cargoes through the generation of vesicular endosomal carriers.

    “SNX3 can recruit retromer onto the endosomal surface, and from here SNX3-retromer regulates the endosome-to-Golgi trafficking of its cargoes through the generation of vesicular endosomal carriers.41,66”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [66]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Through their C-terminal COMM domains, the COMMD subunits form heterodimers.

    “Through their C-terminal COMM domains, the COMMD subunits form heterodimers. 133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    VPS26 is a genetic risk factor for type 2 diabetes.

    “VPS26 is a genetic risk factor for type 2 diabetes.189”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    RME8 interacts with SNX1 and FAM21.

    “RME8 is interacts with SNX1 and FAM21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Retromer and its adaptors are linked with several metabolic and neurodegenerative diseases.

    “Retromer and its adaptors are linked with several other metabolic and neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Enhancing retromer stability with the chaperone 2a improves motor neuron survival and locomotor function in Sod1 G93A mice.

    “Enhancing retromer stability with the chaperone 2a improves motor neuron survival and locomotor function in Sod1 G93A mice.178”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Mutation of RME8 causes autosomal dominant Parkinson's disease that is phenotypically similar to VPS35 mutations.

    “mutation of this protein causes autosomal dominant Parkinson's disease that are phenotypically similar to VPS35 mutations.150”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Retromer supports healthy neuronal function by dendritic spine maintenance and recycling of neuromodulator and neurotransmitter receptors.

    “Retromer also supports healthy neuronal function by other means such as dendritic spine maintenance, and recycling of neuromodulator and neurotransmitter receptors.143,144”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [143]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [144]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The L625P mutation perturbs the VPS35-VPS29 interaction and therefore the stability of the retromer complex.

    “this mutation perturbs the VPS35-VPS29 interaction, and therefore the stability of the retromer complex.161”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The D620N mutant of VPS35 impairs receptor trafficking, lysosomal function, and autophagosome formation.

    “impairs receptor trafficking, lysosomal function, and autophagosome formation.54,95”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Pharmacological stabilization of retromer limits amyloid-b production both in vitro and in vivo.

    “Pharmacological stabilization of retromer limits amyloid-b production both in vitro and in vivo.164,175”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [175]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Retromer components VPS35, VPS26A and VPS29, SNX27, commander/CCC complex members COMMD2, COMMD3 and COMMD4, several lysosomal V-type ATPase components, and the lysosomal protease CTSL are host factors required for SARS-CoV-2 infection.

    “identified retromer components (VPS35, VPS26A, VPS29) and SNX27, as well as the related commander/CCC complex members (COMMD2, -3 and -4), several components of the lysosomal V-type ATPase and the lysosomal protease CTSL as host factors required for SARS-CoV2 infection.187”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The D620N mutant of VPS35 impairs its interaction with FAM21, and thus the WASH complex.

    “The D620N mutant of VPS35 impairs its interaction with FAM21, and thus the WASH complex”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Retromer is critical for autophagy-dependent clearance of tau aggregates and limits tau-induced neurotoxicity.

    “In addition, retromer is critical for autophagy-dependent clearance of tau aggregates, and limits tau-induced neurotoxicity.[166][167][168]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [166]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [167]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [168]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

    Premisenone given

    Retromer is important for mitochondrial dynamics, function, and quality control.

    “Retromer is important for mitochondrial dynamics, function, and quality control.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Retromer deficiency is observed in stem cell-derived motor neurons from amyotrophic lateral sclerosis patients with SOD1 mutations and in transgenic Sod1 G93A mice.

    “Retromer deficiency is also observed in stem cell-derived motor neurons from amyotrophic lateral sclerosis patients with SOD1 mutations and in transgenic Sod1 G93A mice.177,178”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [177]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [178]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The Legionella pneumophila effector RidL outcompetes TBC1D5 and VARP for binding to VPS29 and inhibits retromer-dependent trafficking to promote intracellular growth and replication of the pathogen.

    “The Legionella pneumophila effector RidL outcompetes TBC1D5 and VARP for binding to VPS29 and inhibits retromer-dependent trafficking to promote intracellular growth and replication of the pathogen.179-182”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [179]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [180]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [181]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [182]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The lipid phosphatase MTMR2 interacts with CCDC22 to restrict its phosphorylation at serine 58, which in turn suppresses PtdIns(3)P levels and ensures proper retriever-dependent trafficking.

    “The lipid phosphatase MTMR2 interacts with CCDC22 to restrict its phosphorylation at serine 58, which in turn suppresses PtdIns(3)P levels and ensures proper retriever-dependent trafficking.132,134”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [134]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The influenza A virus effector protein M2 abrogates the Rab7-TBC1D5 interaction by binding to the C-terminus of TBC1D5, which inhibits autophagosome-lysosome fusion and enhances virus secretion.

    “The influenza A virus effector protein M2 abrogates the Rab7-TBC1D5 interaction by binding to the C-terminus of TBC1D5 which inhibits autophagosome-lysosome fusion and enhances virus secretion.185”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    VPS35 has a potential oncogenic function in liver cancer by augmenting the phosphoinositide 3-kinase-AKT-mTORC1 pathway.

    “VPS35 has a potential oncogenic function in liver cancer by augmenting the phosphoinositide 3-kinase-AKT-mTORC1 pathway.190”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The VPS35 D620N mutation increases a-synuclein aggregation, its toxicity, and neuronal loss.

    “The VPS35 D620N mutation increases a-synuclein aggregation, its toxicity, and neuronal loss.[140][141][142]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [140]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [141]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [142]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • The quote only partly states this claim.

    Premisecitation

    These genetic linkage hits failed to reach genome-wide significance in larger and more robust studies.

    “however, these”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [176]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    The mechanisms by which cells fine-tune retromer function to adapt to dynamic changes in nutrient availability, growth factor stimulation, and metabolic state switching are only beginning to be explored.

    “The mechanisms by which cells fine-tune retromer function to adapt to dynamic changes in nutrient availability, growth factor stimulation, and the switching of metabolic states is only beginning to be explored.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Mutations in KIAA0196, which encodes the WASH complex component strumpellin, cause hereditary spastic paraplegia.

    “Mutations in KIAA0196 which encodes the WASH complex component strumpellin cause hereditary spastic paraplegia.192”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    An important aspect of retromer biology that is poorly understood is its upstream regulation.

    “An important aspect of retromer biology that is poorly understood is its upstream regulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    RAB7A mutations cause the axonopathy Charcot-Marie-Tooth 2B disease.

    “RAB7A mutations cause the axonopathy Charcot-Marie-Tooth 2B disease.195”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    SNX27 is depleted in the brains of people with Down's syndrome, which is associated with Alzheimer's disease-like pathology.

    “SNX27 is depleted in the brains of people with Down's syndrome, which is associated with Alzheimer's disease-like pathology.191”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    More than 20 years after its discovery in yeast, we have now begun to understand the function of retromer at the molecular level.

    “More than 20 years after its discovery in yeast, we have now begun to understand the function of retromer at the molecular level.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Mutations in KIAA0196, VPS35L and CCDC22 cause Ritscher-Schinzel syndrome.

    “Interestingly, mutations in KIAA0196 as well as retriever and commander/CCC complex genes VPS35L and CCDC22, respectively, cause Ritscher-Schinzel syndrome.193,194”
    • Also stated in: § Microbial infections. · plain
      “KIAA0196 as well as retriever and commander/CCC complex genes VPS35L and CCDC22, respectively, cause Ritscher-Schinzel syndrome.193,194”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [193]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [194]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    The mechanisms governing retromer recruitment to endosomes, engagement with adaptors, and cargo selection/sorting have been characterized in much greater detail.

    “The mechanisms that govern its recruitment to endosomes, engagement with adaptors, and cargo selection/sorting have been characterized in much greater detail.”
    Quote in the paperNot a substantial claim
62 of 62

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The VPS35 sorting motif has two different sequences

    Minor

    The text names the conserved VPS35 motif as PYLRL, while the title of a cited reference names it PRLYL. The sequences differ at two positions.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1038/s41380-019-0364-x

    Major

    The cited work was retracted on 2022-10-18 (notice 10.1038/s41380-022-01814-1), before this paper was published (2023-06-23). Its authors could have known.

    Cited work 10.1038/s41380-019-0364-x · retracted 2022-10-18 · notice 10.1038/s41380-022-01814-1 · this paper published 2023-06-23

  • Cites a retracted work: 10.1038/s41380-019-0453-x

    Major

    The cited work was retracted on 2023-01-25 (notice 10.1038/s41380-023-01973-9), before this paper was published (2023-06-23). Its authors could have known.

    Cited work 10.1038/s41380-019-0453-x · retracted 2023-01-25 · notice 10.1038/s41380-023-01973-9 · this paper published 2023-06-23

2 of 2

Citations

Cites

2 retracted

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.1074/jbc.m113.533240 · DOI
  2. 10.1186/s13041-014-0073-y · DOI

Cited by

Sorted by citations

Related

Metadata

Authors
Carosi, J. M., Denton, D., Kumar, S., & Sargeant, T. J.
Affiliations
  • University of South Australia (AU)
  • South Australian Health and Medical Research Institute (AU)
Corresponding author
Sargeant, Timothy J.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2023-06-23
Volume
43
Issue
7
Pages
317-334
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1080/10985549.2023.2222053
PMC
PMC10348044
OpenAlex
W4381716022
Cited by
36
References
196
Citations by year
2026: 10 · 2025: 10 · 2024: 15 · 2023: 1
FWCI
0.99
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • UniSA Research Outputs Repository (University of South Australia) (submittedVersion)
Funders
  • Lysosomal Health in Ageing at SAHMRI
  • Research Training Stipend.
  • Australian Government
  • UniSA
  • National Health and Medical Research Council (1124490)
  • Australian Research Council Discovery Project (DP10100665)
  • NHMRC Senior Principal Research Fellowship (GNT1103006)
  • L3 Investigator Grant (2007739)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
retromer complex, receptor recycling, endosomal sorting, endosome-to-Golgi transport, adaptor proteins, cargo selection, endolysosomal system, neurodegenerative diseases, metabolic disorders, microbial infection
MeSH terms
Animals, Cell Membrane, Golgi Apparatus, Endosomes, Saccharomyces cerevisiae, Protein Transport, trans-Golgi Network

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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