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Cited by 169Cellular transport and secretionAutophagy in Disease and TherapyCalcium signaling and nucleotide metabolism

The DOI matches its Crossref record; 116 of the 116 references it cites were found in a registry or an index; none of the 116 sources its claims cite is checked for support yet.

Endosomal Retrieval of Cargo: Retromer Is Not Alone

Open access
McNally, Kerrie E., Cullen, Peter J.·2018·Trends in Cell Biology
DOI 10.1016/j.tcb.2018.06.005
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Abstract

Endosomes are major protein sorting stations in cells. Endosomally localised multi-protein complexes sort integral proteins, including signaling receptors, nutrient transporters, adhesion molecules, and lysosomal hydrolase receptors, for lysosomal degradation or conversely for retrieval and subsequent recycling to various membrane compartments. Correct endosomal sorting of these proteins is essential for maintaining cellular homeostasis, with defects in endosomal sorting implicated in various human pathologies including neurodegenerative disorders. Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. While retromer is a major player in endosomal retrieval and recycling, several studies have recently identified retrieval mechanisms that are independent of retromer. Here, we review endosomal retrieval complexes, with a focus on recently discovered retromer-independent mechanisms.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that endosomal cargo retrieval is mediated by multiple conserved multiprotein complexes—retromer, retriever, CCC, and WASH—rather than by retromer alone. It synthesizes evidence for retromer-independent retrieval pathways, spatial segregation of retrieval and degradative endosomal subdomains, and links to human disease.

Key findings

  • Four major evolutionarily conserved endosomal retrieval complexes—retromer, retriever, the CCC complex, and the WASH complex—drive sequence-dependent retrieval of cargo away from lysosomal degradation. Retromer regulates over 100 integral plasma membrane proteins, SNX17 regulates over 200 cargo, and retriever is likely responsible for at least an additional 200 integral proteins.
  • Retriever is a retromer-like heterotrimer of DSCR3, C16orf62, and VPS29; it functions independently of retromer and requires the CCC and WASH complexes for endosomal localization and function.
  • The WASH complex organizes endosomal retrieval subdomains through branched actin polymerization and recruits the CCC complex via the FAM21 tail; CCC then recruits retriever, where SNX17 acts as a cargo adaptor for cargo such as α5β1 integrin, LDLR, and LRP1.
  • Mutations in these retrieval complexes are associated with human pathologies including intellectual disability, developmental disorders, and neurodegeneration; homozygous knockouts of COMMD1, COMMD6, COMMD9, COMMD10, WASH1, and strumpellin are embryonic lethal in mice.

Methods

  • Narrative review; no experimental design or primary data are reported.
  • Synthesizes published studies across model systems including yeast, human cultured cells, HeLa cells, mouse embryonic fibroblasts, Drosophila, C. elegans, Dictyostelium, and mouse models, along with proteomic, structural, and evolutionary analyses.
  • Main analysis is conceptual synthesis and model-building of endosomal retrieval pathways.

Limitations

  • The paper states many outstanding questions remain, including the precise role of retromer in endosome-to-TGN transport, whether retriever binds cargo directly, how downstream carrier formation/scission/transport is mediated, what regulates retrieval complexes, and whether undiscovered complexes exist; retromer-independent WASH recruitment and CCC cargo engagement are also poorly characterized.
  • Evident from the text: as a review, it provides no new experimental data, and some proposed models—such as the COMMander super-complex and lipid-binding roles of COMMDs—are speculative and require further biochemical evidence.

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

Integrity signals

Registry

Crossref · 10.1016/j.tcb.2018.06.005

Cites

116 of 116 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 116 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    Together retromer, retriever, the CCC complex and the WASH complex provide a mechanism for retromer-independent endosomal sorting of additional cargo.

    “Importantly, together these complexes provide a mechanism for retromer-independent endosomal sorting of additional cargo [14].”
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  • Premisecitation

    Not all cargo require retromer for their retrieval and recycling.

    “However, not all cargo require retromer for their retrieval and recycling [13][14][15][16].”
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  • Premisenone given

    The WASH complex organizes the retrieval sub-domain by acting as an endosomal scaffold for the recruitment of additional multi-protein retrieval complexes and regulators of endosomal sorting to the retrieval sub-domain.

    “Moreover the WASH complex also organizes the retrieval sub-domain by acting as an endosomal scaffold for the recruitment of additional multi-protein retrieval complexes and regulators of endosomal sorting to the retrieval sub-domain.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In Dictyostelium discoideum, the WASH complex is required for recycling of phagocytic receptors from phagosomes to the plasma membrane.

    “In Dictyostelium discoideum, the WASH complex is required for recycling of phagocytic receptors from phagosomes to the plasma membrane [39].”
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  • Premisecitation

    WASH and its ability to polymerize actin was required for the removal of v-ATPase from lysosomal membranes, to allow lysosome neutralization prior to exocytosis of indigestible material.

    “Moreover, WASH and its ability to polymerize actin was required for the removal of v-ATPase from lysosomal membranes, to allow lysosome neutralization prior to exocytosis of indigestible material [40].”
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    Premisecitation

    In human cultured cells, retromer regulates cell surface levels of over 100 integral plasma membrane proteins and mediates recycling of cargo from the endosome to the TGN and to lysosomal-related organelles.

    “In human cultured cells, retromer regulates cell surface levels of over 100 integral plasma membrane proteins as well as mediating recycling of cargo from the endosome to the TGN and to lysosomal-related organelles [1,2,12].”
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    Interpretationcitation

    Purified WASH complex displayed the ability to associate with liposomes and the carboxy-terminal tail of FAM21 was shown to bind PI3P and PI(3,5)P2, suggesting that intrinsic lipid association of the WASH complex may be important for retromer-independent recruitment to endosomal membranes.

    “However, purified WASH complex displayed the ability to associate with liposomes and the carboxy-terminal tail of FAM21 was shown to bind to PI3P and PI(3,5)P2, phosphoinositides found enriched on the cytosolic leaflet of early and late endosomes, suggesting that intrinsic lipidassociation of the WASH complex may be important for retromer-independent recruitment to endosomal membranes [26,27,44].”
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  • It may state two separate claims as one.

    Premisecitation

    Retromer can retrieve and recycle cargo back to the plasma membrane and this often occurs through association with SNX27, which recognises a PDZbm within the cytosolic domain of integral proteins.

    “In addition, retromer can retrieve and recycle cargo back to the plasma membrane and this often occurs through association with a distinct retromer cargo adaptor, SNX27, which recognises a PDZbm within the cytosolic domain of integral proteins [12,38,63,64].”
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  • It may state two separate claims as one.

    Premisecitation

    The CCC complex colocalizes with retromer, retriever and the WASH complex on endosomes and is required for the endosomal retrieval and recycling of LDLR, Notch2 and ATP7A to the plasma membrane.

    “The CCC complex colocalizes with retromer, retriever and the WASH complex on endosomes and is required for the endosomal retrieval and recycling of LDLR, Notch2 and ATP7A to the plasma membrane [14,17,18,85].”
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    Premisecitation

    Retromer directly binds to the multiple LFa repeats in the carboxy-terminal tail of FAM21 and this was reported to be sufficient and necessary for endosomal recruitment of the WASH complex.

    “Retromer directly binds to the multiple LFa (leucine-phenylalanine-a series of acidic residues) repeats in the carboxy-terminal tail of FAM21 and this was reported to be sufficient and necessary for endosomal recruitment of the WASH complex [31,32,42,43].”
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    Interpretationcitation

    β2-adrenergic receptors that lack a PDZbm but instead harbor an actin-binding domain can recycle normally, indicating that interactions between endosomal actin and cargo may be sufficient for recycling.

    “Interestingly, β2-adrenergic receptors that lack a PDZbm (PDZ binding motif), required for retrieval and recycling, but instead harbor an actin-binding domain can recycle normally, indicating that interactions between endosomal actin and cargo may be sufficient for recycling [10].”
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    Interpretationcitation

    Super-resolution imaging established that retromer cargo destined for the plasma membrane and the TGN are sorted into the same tubular carriers, suggesting that recycling to either membrane occurs downstream of retromer.

    “Recently super-resolution imaging established that retromer cargo destined for the plasma membrane and the TGN are sorted into the same tubular carriers, suggesting that recycling to either membrane occurs downstream of retromer [65].”
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  • It may state two separate claims as one.

    Premisecitation

    Retriever and retromer undertake distinct cargo retrieval itineraries but are localized to the same endosomal retrieval sub-domain.

    “Retriever and retromer undertake distinct cargo retrieval itineraries but are localized to the same endosomal retrieval sub-domain [14,17].”
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    Premisecitation

    Depletion of retromer results in lysosomal degradation of GLUT1, whereas suppression of SNX-BARs results in endosomal accumulation of GLUT1.

    “For example, depletion of retromer results in lysosomal degradation of the glucose transporter GLUT1, whereas suppression of SNX-BARs, which are important for carrier formation, results in endosomal accumulation of the transporter [12].”
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    Premisecitation

    Retromer does not contain any membrane binding domains and instead relies upon interactions with SNX3 and the late endosomal/lysosomal Rab GTPase Rab7 for membrane association to early and early-to-late transitioning endosomes.

    “Retromer does not contain any membrane binding domains and instead relies upon interactions with SNX3 and the late endosomal/lysosomal Rab GTPase Rab7 for membrane association to early and early-to-late transitioning endosomes (Figure 3) [82][83][84].”
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  • It may state two separate claims as one.

    Premisecitation

    SNX17 and SNX27 both contain a FERM domain but SNX17 lacks the amino-terminal PDZ domain found in SNX27 required for binding to PDZbm in cargo and for interactions with retromer.

    “SNX17 and SNX27 both contain a FERM (4.1/ezrin/radixin/moesin) domain but SNX17 lacks the amino-terminal PDZ domain found in SNX27 required for binding to PDZbm in cargo and for interactions with retromer [63,74,75].”
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  • It may state two separate claims as one.

    Interpretationcitation

    Upon suppression or knock-out of retromer, retriever, WASH or CCC complexes, cargo are degraded in lysosomes, suggesting that in the absence of these sorting complexes, cargo degradation may be the default pathway.

    “Interestingly, upon suppression or knock-out of retromer, retriever, the WASH or CCC complexes (see subsequent discussions), cargo are degraded in lysosomes suggesting that in the absence of these sorting complexes, cargo degradation may be the default pathway [12,14].”
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Depletion of components of the WASH complex resulted in elongated endosomal recycling tubules, suggesting that the WASH complex is required for tubule scission.

    “Besides the role of the WASH complex and actin in endosomal organization, it was reported that depletion of components of the WASH complex resulted in elongated endosomal recycling tubules, suggesting that the WASH complex is required for tubule scission [26,35].”
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  • It may state two separate claims as one.

    Interpretationreasoning

    Even multiple SNX-retromer complexes are unlikely to account for the sequence-dependent retrieval and recycling of all cargo transiting through the endosomal system, suggesting that additional retrieval and recycling pathways exist.

    “Yet, even multiple SNX-retromer complexes are unlikely to account for the sequencedependent retrieval and recycling of all cargo transiting through the endosomal system, suggesting that additional retrieval and recycling pathways exist.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The WASH complex promotes endosomal branched actin polymerization and plays essential roles in both retromer-dependent and retromer-independent pathways.

    “The WASH complex, which promotes endosomal branched actin polymerization, plays essential roles in both retromerdependent and retromer-independent pathways, demonstrating that the WASH complex is fundamental for endosomal cargo sorting [14,[17][18][19].”
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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

    Retromer is an ancient endosomal sorting complex, conserved in all eukaryotes.

    “Retromer is an ancient endosomal sorting complex, conserved in all eukaryotes [45].”
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  • It may state two separate claims as one.

    Premisecitation

    In fibroblasts derived from WASH knock-out mice and melanocytes from strumpellin knock-out mice, the endosomal and lysosomal networks become collapsed to the peri-nuclear region, suggesting that the WASH complex is important for the spatial organization of the endo-lysosomal system.

    “Strikingly, in fibroblasts derived from WASH knock-out mice and melanocytes from strumpellin knock-out mice, the endosomal and lysosomal networks become collapsed to the peri-nuclear region suggesting that the WASH complex is also important for the spatial organization of the endo-lysosomal system although the underlying mechanisms remain unknown [33,34].”
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  • It may state two separate claims as one.

    Premisecitation

    Knock-out of VPS35, the core component of retromer, does not give this phenotype, demonstrating that retriever-dependent sorting of cargo is independent of retromer.

    “Importantly, knock-out of VPS35, the core component of retromer, does not give this phenotype demonstrating that retriever-dependent sorting of cargo is independent of retromer [14].”
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  • It may state two separate claims as one.

    Premisecitation

    The FERM domain of SNX17 mediates binding to NPx(Y/F) motifs within the cytosolic tails of cargo such as LRP1, LDLR and α5β1 integrin, and upon suppression of SNX17 these cargo are degraded in lysosomes.

    “The FERM domain of SNX17 mediates the binding to NPx(Y/F) motifs within the cytosolic tails of cargo such as LRP1 (Low density lipoprotein receptor-related protein 1), LDLR and α5β1 integrin and upon suppression of SNX17, these cargo are degraded in lysosomes [16,[76][77][78].”
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  • It may state two separate claims as one.

    Premisecitation

    Retromer engages cargo containing a ØX(L/M) motif in their cytosolic tail and VPS26 directly binds a FANSHY motif within the cytoplasmic tail of sorLA.

    “Retromer engages cargo containing a ØX(L/M) (where Ø represents an aromatic amino acid and x represents any amino acid) motif in their cytosolic tail and VPS26 directly binds a FANSHY motif within the cytoplasmic tail of sorLA [52,[57][58][59].”
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  • It may state two separate claims as one.

    Premisecitation

    SNX3 can directly engage cargo such as the yeast iron transporter Fet3p-Ftr1p and Wntless while simultaneously associating with retromer for retrieval of these cargo away from degradation and for their recycling back to the TGN.

    “Whilst some cargo have been reported to directly bind to retromer, it was discovered that a 'cargo adaptor', SNX3, could directly engage cargo such as the yeast iron transporter Fet3p-Ftr1p and Wntless whilst simultaneously associating with retromer for retrieval of these cargo away from degradation and for their recycling back to the TGN [59][60][61][62].”
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    Premisecitation

    Depolymerization of endosomal actin causes distinct WASH labelled retrieval subdomains to merge, indicating that endosomal actin is important for the formation and maintenance of retrieval subdomains.

    “Depolymerization of endosomal actin causes distinct WASH labelled retrieval subdomains to merge indicating that endosomal actin is important for the formation and maintenance of retrieval subdomains [23].”
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  • It may state two separate claims as one.

    Premisecitation

    In a retromer knock-out HeLa cell line, a significant proportion of FAM21 remains associated with the endosomal network, establishing that in human cells the endosomal association of the WASH complex is mediated through both retromer-dependent and retromer-independent mechanisms.

    “However, in a retromer knock-out HeLa cell line, a significant proportion of FAM21 remains associated with the endosomal network, establishing that in human cells the endosomal association of the WASH complex is mediated through both retromerdependent and retromer-independent mechanisms [14].”
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  • It may state two separate claims as one.

    Interpretationcitation

    SNX17 interactions with the CCC complex are dependent upon retriever, suggesting that SNX17 interacts indirectly with the CCC complex through retriever.

    “SNX17 interactions with the CCC complex are dependent upon retriever, suggesting that SNX17 interacts indirectly with the CCC complex through retriever [14].”
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  • 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

    The CCC complex interacts with and recruits retriever to the retrieval subdomain.

    “The CCC complex interacts with and recruits retriever to the retrieval subdomain.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The core COMMander complex consists of 14 proteins: CCDC22, CCDC93, COMMD 1-10, C16orf62 and DSCR3.

    “The current evidence for COMMander has been recently reviewed, suggesting that that the core COMMander complex consists of 14 proteins: CCDC22, CCDC93, COMMD 1-10, C16orf62 and DSCR3 [89].”
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    VPS29 can bind to regulatory factors such as TBC1D5, a Rab7 GAP and VARP.

    “VPS29 can also bind to regulatory factors such as TBC1D5, a Rab7 GAP and VARP.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Components of the CCC complex directly interact with the tail of FAM21, an interaction which is necessary for CCC complex localization.

    “However, like retromer, components of the CCC complex have been shown to directly interact with the tail of FAM21, an interaction which is necessary for CCC complex localization [17,31].”
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  • It may state two separate claims as one.

    Premisecitation

    Knock-out of FAM21 results in the loss of endosomal association of retriever and consequently lysosomal degradation of α5β1 integrin.

    “Extending this further, knock-out of FAM21, which recruits the CCC complex to endosomes, also results in the loss of endosomal association of retriever and consequently lysosomal degradation of α5β1 integrin [14].”
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  • It may state two separate claims as one.

    Premisecitation

    Retriever can be purified from insect cells as a stable heterotrimer, and the CCC complex is required for retriever localization, protein stability and function.

    “Whilst retriever can be purified from insect cells as a stable heterotrimer, the CCC complex is required for retriever localization, protein stability and function [14,103].”
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  • It may state two separate claims as one.

    Interpretationreasoning

    Mutations in CCC and WASH complex subunits present very similar patient phenotypes, such as intellectual disability, suggesting a shared mechanism of pathology.

    “Interestingly, mutations in CCC and WASH complex subunits present very similar patient phenotypes, such as intellectual disability, suggesting a shared mechanism of pathology (Table 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    The current model suggests that the WASH complex is recruited to endosomes in retromer-dependent and retromer-independent mechanisms, where it recruits the CCC complex through interactions with FAM21; the CCC complex then recruits retriever to the retrieval sub-domain of endosomes where it can engage SNX17 and its bound cargo, driving retrieval of cargo away from degradation.

    “The current model suggests that the WASH complex is recruited to endosomes in retromer-dependent and retromer-independent mechanisms, where it recruits the CCC complex through interactions with FAM21.The CCC complex then recruits retriever to the retrieval sub-domain of endosomes where it can engage SNX17 and its bound cargo, driving retrieval of cargo away from degradation (Figure 3).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    COMMD9 and COMMD1 knock-out mice, whilst both embryonic lethal, display different phenotypes indicating that they are not completely redundant with one another.

    “Consistent with this idea, COMMD9 and COMMD1 knock-out mice, whilst both embryonic lethal, display different phenotypes indicating that they are not completely redundant with one another [85,95].”
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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.

    Premisenone given

    Sequence motifs within cytosolic domains of cargo are recognized by retromer, either directly via a phi-x(L/M) motif or indirectly through the cargo adaptors SNX3 and SNX27, the latter of which binds to cargo containing a PDZbm.

    “Sequence motifs within cytosolic domains of cargo are recognized by retromer, either directly via a ϕx(L/M) motif (where ϕ represents an aromatic residue and x represents any residue) or indirectly through the cargo adaptors SNX3 and SNX27, the latter of which binds to cargo containing a PDZbm.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Retromer is recruited to the endosomal membrane through interactions with SNX3 and GTP-bound Rab7a.

    “Retromer is recruited to the endosomal membrane through interactions with SNX3 and GTP-bound Rab7a.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Wash1 knock-out MEFs display endosomal accumulation of LDLR and increased degradation of the receptor, which can be rescued through treatment with bafilomycin.

    “In agreement with the WASH complex being important for the function of the CCC complex, Wash1 knock-out MEFs display endosomal accumulation of LDLR and increased degradation of the receptor, which can be rescued through treatment with bafilomycin, which prevents lysosomal acidification and thus pH-dependent degradation [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18]

      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.

    Interpretationnone given

    Retriever requires the CCC and WASH complexes for endosomal localisation and function.

    “Retriever requires the CCC and WASH complexes for endosomal localisation and function”
    Quote in the paperNot a substantial claim

  • 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

    SNX17 associates with endosomal membranes through its PX domain and engages cargo, such as alpha5beta1 integrin, containing NPxY or NPxF motifs.

    “SNX17 associates with endosomal membranes through its PX domain and engages cargo, such as α5β1 integrin, containing NPxY or NPxF motifs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    Mutations in these multi-protein complexes are increasingly associated with human pathologies including neurodegeneration and developmental disorders.

    “Mutations in these multi-protein complexes are increasingly associated with human pathologies including neurodegeneration and developmental disorders.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Recombinant COMMD1 was found to bind to liposomes containing PI(4,5)P2, an interaction which required the COMM domain and promoted COMMD1 oligomerisation.

    “Recombinant COMMD1 was found to bind to liposomes containing PI(4,5)P2, an interaction which required the COMM domain and promoted COMMD1 oligomerisation [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96]

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

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

    Interpretationnone given

    Retriever is a retromer-like complex that functions independently of retromer.

    “Retriever is a retromer-like complex that functions independently of retromer”
    Quote in the paperNot a substantial claim

  • 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

    The endosomal retrieval sub-domain and degradative sub-domains are spatially segregated on endosomal membranes; degradative sub-domains contain ESCRT complexes and retrieval sub-domains contain retriever, retromer and the WASH and CCC complexes.

    “The endosomal retrieval sub-domain 'Degradative' sub-domains containing ESCRT complexes and 'retrieval' sub-domains containing retriever, retromer and the WASH and CCC complexes are spatially segregated on endosomal membranes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    Reintroduction of a WASH mutant that cannot activate Arp2/3 into Wash1 knock-out MEFS did not rescue LDLR from lysosomal degradation, suggesting that branched actin polymerization is essential for CCC complex-dependent recycling of cargo.

    “Furthermore, the reintroduction of a WASH mutant, that cannot activate Arp2/3, into Wash1 knock-out MEFS did not rescue LDLR from lysosomal degradation, suggesting that branched actin polymerization is essential for CCC complex-dependent recycling of cargo [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18]

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

  • It may state two separate claims as one.

    Premisenone given

    The WASH complex is recruited to endosomal membranes through interactions of the FAM21 tail with retromer and also through unidentified retromer-independent mechanisms.

    “The WASH complex is recruited to endosomal membranes through interactions of the FAM21 tail (represented as a black wavy line) with retromer and also through unidentified retromer-independent mechanisms.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Suppression of CCDC22 or CCDC93 results in the lysosomal degradation of α5β1 integrin, indicating that SNX17, retriever and the CCC complex are functionally linked.

    “Furthermore, suppression of CCDC22 or CCDC93 results in the lysosomal degradation of α5β1 integrin, indicating that SNX17, retriever and the CCC complex are functionally linked.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Retromer is a key orchestrator of endosomal sorting but retromer-independent pathways exist.

    “Retromer is a key orchestrator of endosomal sorting but retromer-independent pathways exist”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    Evolutionary conservation analysis infers that the WASH, CCC and retriever complexes co-evolved, consistent with the notion that these complexes depend on each other for localization and function.

    “Evolutionary conservation analysis infers that the WASH, CCC and retriever complexes co-evolved, consistent with the notion that these complexes depend on each other for localization and function [14,28,89].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14]

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

    • cites [28]

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

    • cites [89]

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

  • It may state two separate claims as one.

    Interpretationcitation

    The COMM domain is essential for interactions between COMMD1 and the CCC complex subunits CCDC22 and CCDC93, a mechanism which probably underlies how every COMMD protein has the ability to associate with CCDC22 and CCDC93.

    “In addition, the COMM domain has been shown to be essential for interactions between COMMD1 and the CCC complex subunits CCDC22 and CCDC93, a mechanism which probably underlies how every COMMD protein has the ability to associate with CCDC22 and CCDC93 [17,86].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17]

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

    • cites [86]

      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

    SNX17 is a cargo adaptor for retriever, associating with retriever through its flexible carboxy-terminal tail.

    “SNX17 is a cargo adaptor for retriever, associating with retriever through its flexible carboxy-terminal tail.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Genome-wide human interaction networks and phylogenetic analyses have suggested the presence of a large, ancient, multi-protein complex named 'COMMander' because of the presence of a large number of COMMD proteins.

    “Genome-wide human interaction networks and phylogenetic analyses have suggested the presence of a large, ancient, multi-protein complex named 'COMMander' because of the presence of a large number of COMMD proteins [28,92,101,102].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [28]

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

    • cites [92]

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

    • cites [101]

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

    • cites [102]

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

  • It may state two separate claims as one.

    Premisecitation

    COMMD1 is involved in ATP7A and LDLR recycling.

    “Moreover, it has recently been shown that the CCC complex containing COMMD9 dimerized to COMMD5 or COMMD10 was involved in the retrieval and recycling of Notch2 to the plasma membrane [85], whereas COMMD1 is involved in ATP7A and LDLR recycling [17,18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17]

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

    • cites [18]

      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

    The pentameric WASH complex activates Arp2/3, which polymerizes branched actin on the endosomal membrane.

    “The pentameric WASH complex (individual subunits are not shown for simplicity) activates Arp 2/3, which polymerizes branched actin on the endosomal membrane.”
    Quote in the paperNot a substantial claim
52 of 52

  • The paper relies on this without support.

    The recycling tubules display a high surface area to low volume ratio.

    “The recycling tubules display a high surface area to low volume ratio”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The itinerary of PCSK9-LDLR to the lysosome is spatially separated from the LDLR recycling route.

    “These data indicate that the itinerary of PCSK9-LDLR to the lysosome is spatially separated from the LDLR recycling route (11,23,63).”

    From The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance (2019) · cites this paper as [11]

    The section “Retrieval and degradative functions of the endosome are spatially segregated” says that degradative and retrieval complexes occupy distinct endosomal subdomains, though it describes cargo segregation as a possibility. “The CCC complex” identifies LDLR as recycling cargo. The paper does not establish that PCSK9-bound LDLR specifically follows a spatially separate itinerary to the lysosome. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • SNX17-dependent recycling requires the Retriever complex, the CCC complex, and the actin-regulatory WASH complex.

    “SNX17-dependent recycling requires the Retriever complex (VPS35L, VPS26C, and VPS29), the CCC complex (COMMD/CCDC22/CCDC93), and the actin-regulatory WASH complex”

    From PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity (2025) · cites this paper as McNally and Cullen, 2018

  • Retriever shares similarities with Retromer, composed of related VPS35L and VPS26C subunits and the shared VPS29 protein, and associates with one divergent adaptor SNX17.

    “Although Retriever shares similarities with Retromer, composed of related VPS35L and VPS26C subunits and the shared VPS29 protein, and associates with one divergent adaptor SNX17,2,3,6,15”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [3]

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.

  • Table 1 omits a stated WASH-complex subunit variant

    Minor

    The main text lists FAM21A, FAM21B and FAM21C as WASH-complex subunit variants, but Table 1 lists only FAM21A and FAM21C under subunits.

  • Retromer cargo motif is defined differently

    Minor

    Table 1 defines Ø as any hydrophobic amino acid, whereas the main text defines it as an aromatic amino acid. The table therefore describes a broader motif than the text.

2 of 2

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Metadata

Authors
McNally, K. E., & Cullen, P. J.
Affiliations
University of Bristol (GB)
Corresponding author
Cullen, Peter J.
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2018-10
Volume
28
Issue
10
Pages
807-822
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2018.06.005
OpenAlex
W2885672643
Cited by
169
References
115
Citations by year
2026: 13 · 2025: 25 · 2024: 22 · 2023: 16 · 2022: 22 · 2021: 27 · 2020: 22 · 2019: 19 · 2018: 3
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by-nc-nd)
  • Explore Bristol Research (submittedVersion, cc-by-nc-nd)
Funders
  • Wellcome Trust (104568/Z/14/2, 083474)
  • Medical Research Council (MR/P018807/1, MR/L007363/1)
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 › Physiology › Calcium signaling and nucleotide metabolism
Keywords
retromer complex, endosomal sorting, protein recycling, lysosomal degradation, neurodegenerative diseases
MeSH terms
Animals, Humans, Membrane Proteins, Endosomes

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