ENTR1

UniProt ID: A0A8C4MKL2
Organism: Equus asinus
Review Status: COMPLETE
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Gene Description

ENTR1 (endosome-associated-trafficking regulator 1, also known as SDCCAG3) is a cytoplasmic coiled-coil protein of early and recycling endosomes, conserved as a single-copy gene across vertebrates (PANTHER family PTHR31259). Characterized in human cells, it is recruited to retromer-decorated endosomes through the WASH complex and has been implicated in SNX27-retromer-dependent recycling of cargo such as GLUT1 to the cell surface; it also relocates to the midbody during cytokinesis, where it acts with the phosphatase PTPN13 and the ArfGAP GIT1, and localizes to the centrosome and ciliary basal body, where it binds IFT88 and supports cilium assembly and ciliary delivery of polycystin-2. The donkey entry A0A8C4MKL2 (356 aa) conserves the C-terminal ENTR1 coiled-coil region (81% identity to human ENTR1) but lacks the segment corresponding to human residues 9-85 and does not begin with methionine, so it most likely represents an N-terminally incomplete gene model of the donkey ENTR1 gene; the missing segment overlaps the N-terminal region that mediates basal-body targeting, IFT88 binding and GIT1 binding in human ENTR1.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005769 early endosome
IEA
GO_REF:0000118 		ACCEPT
Summary: Early endosome localization is experimentally established for human ENTR1 and is the principal steady-state location of the protein.
Reason: Human ENTR1 is primarily localized at the early/recycling endosomal compartment (PMID:23108400) and the same term is an IBA on human ENTR1 (PAINT node PTN002039065), so PAINT curators judged it ancestral to the clade. Donkey A0A8C4MKL2 is in PTHR31259:SF3; human ENTR1 sits in the hominid-only split SF6, but both are the single ENTR1 ortholog (a human ENTR1 fragment, A0A0A0MRP9, scores into SF3), so the subfamily difference is an HMM partition within one orthologous lineage, not a paralog boundary. The conserved C-terminal coiled-coil region is retained in this gene model.
Supporting Evidence:
file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt
Early endosome {ECO:0000269|PubMed:23108400}.
PMID:23108400
SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment
PMID:27767179
is a recently described novel endosomal protein mainly localized at early and recycling endosomes
file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS-rereview.md
| A0A0A0MRP9 | Homo sapiens (Human) | 223 | unreviewed | PTHR31259;PTHR31259:SF3; |
GO:0005813 centrosome
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: Centrosome localization is reported for human ENTR1 and propagated by PAINT; it accompanies the ciliary role rather than the endosomal one.
Reason: Human ENTR1 colocalizes with IFT88 and pericentrin at the centrosome (PMID:27767179) and the term is an IBA on human ENTR1 (PTN002039065). It is a secondary localization; in addition, the donkey entry lacks the N-terminal region that in human directs basal-body (mother centriole) targeting, so the localization holds for the gene rather than being expected of this truncated sequence model.
Supporting Evidence:
file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt
Colocalizes with IFT88 and pericentrin at the centrosome
file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md
Paired coverage is 81.61% of the human sequence and 99.72% of the donkey sequence.
GO:0030496 midbody
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: Midbody localization during cytokinesis is reported for human ENTR1.
Reason: Human ENTR1 accumulates at the midbody during cytokinesis and colocalizes with PTPN13 there (PMID:23108400); PAINT propagated the term from human (PTN002039065). It is a cell-cycle-stage localization accompanying a non-core role.
Supporting Evidence:
PMID:23108400
SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis
file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt
During cytokinesis colocalized with PTPN13 at the midbody
GO:0032465 regulation of cytokinesis
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: Human ENTR1 is implicated in regulating cytokinesis together with PTPN13 and GIT1.
Reason: In human cells both overexpression and depletion of ENTR1 increase multinucleation, and ENTR1 forms a complex with PTPN13 and binds GIT1 (PMID:23108400, IDA in human GOA); PAINT propagated the term (PTN002039065). The evidence is perturbation-based and the mechanism is undefined, so this is kept as a secondary process. The GIT1-binding N-terminus is absent from this donkey sequence model.
Supporting Evidence:
PMID:23108400
Overexpression as well as downregulation correlates with the generation of multinucleate cells
file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt
Involved in the regulation of cytokinesis; the function may involve PTPN13 and GIT1
GO:0036064 ciliary basal body
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: Human ENTR1 localizes to the basal body of primary cilia through its N-terminal 100 residues, which are largely missing from this donkey entry.
Reason: The localization is experimentally established in human (PMID:27767179) and was propagated by PAINT (PTN004793274), a fair gene-level transfer to donkey ENTR1. However, the targeting determinant (human aa 1-100) is mostly absent from A0A8C4MKL2, so this particular sequence model would not be expected to reach the basal body on its own.
Supporting Evidence:
PMID:27767179
Amino acids 1-100 of SDCCAG3 are necessary and sufficient for basal body localization
file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md
Paired coverage is 81.61% of the human sequence and 99.72% of the donkey sequence.
GO:0045724 positive regulation of cilium assembly
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: ENTR1 knockdown in human cells reduces cilia number and length; the effect depends on the N-terminal region absent from this donkey model.
Reason: Human IMP evidence (PMID:27767179) supports a role in ciliogenesis, propagated by PAINT (PTN004793274); the Delta1-100 construct failed to rescue, so the role maps to the N-terminus that this entry lacks. Retained as a non-core, gene-level process.
Supporting Evidence:
PMID:27767179
decreased expression levels of SDCCAG3 correlate with decreased ciliary length and a reduced percentage of ciliated cells
GO:0055037 recycling endosome
IEA
GO_REF:0000118 		ACCEPT
Summary: Recycling endosome localization is experimentally established for human ENTR1.
Reason: Human ENTR1 is primarily localized at the early/recycling endosomal compartment (PMID:23108400; PMID:27767179) and the term is an IBA on human ENTR1 (PTN002039065). Same orthology reasoning as for early endosome.
Supporting Evidence:
PMID:23108400
SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment
PMID:27767179
is a recently described novel endosomal protein mainly localized at early and recycling endosomes
GO:1903566 positive regulation of protein localization to cilium
IEA
GO_REF:0000118 		KEEP AS NON CORE
Summary: Human ENTR1 is required for ciliary localization of polycystin-2.
Reason: Supported by human IMP data (PMID:27767179) and propagated by PAINT (PTN004793274). Non-core, and gene-level given the missing N-terminal region in this sequence model.
Supporting Evidence:
PMID:27767179
we demonstrate that SDCCAG3 is important for ciliary localization of the membrane protein Polycystin-2

Core Functions

Endosome-associated coiled-coil protein that resides on early and recycling endosomes, where (in human cells) it is recruited to retromer-decorated membranes via the WASH complex and has been implicated in endosome-to-plasma-membrane recycling of SNX27-retromer cargo such as GLUT1.

Cellular Locations:
recycling endosome early endosome
Supporting Evidence:
  • PMID:23108400
    SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment
  • PMID:24980502
    Together, these data establish that the association of ANKRD50, SDCCAG3, and RME-8 to retromer is mediated through binding to the WASH complex, and for SDCCAG3 this is necessary for targeting to retromer-labeled endosomes.

References

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Suggested Questions for Experts

Q: Does the donkey ENTR1 locus encode a full-length protein with the N-terminal basal-body-targeting region, and is A0A8C4MKL2 an incomplete gene model or a genuine N-terminally truncated isoform?

Q: Human ENTR1 carries an IMP annotation to GO:0032456 endocytic recycling (PMID:25278552, 2014), yet PAINT curators propagated its endosome, cytokinesis and cilium terms (2019, 2024) but not endocytic recycling. Was that omission deliberate (the SDCCAG3 knockdown phenotype is cargo-selective and modest), and should the recycling role be represented at the family level?

Q: Is the hominid-restricted PANTHER subfamily split (human ENTR1 in PTHR31259:SF6, other mammals in SF3) biologically meaningful, or an HMM partition within a single orthologous lineage?

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · ENTR1-protnlm-predictions-review.yaml · Review status: COMPLETE

Assessment of 2 ProtNLM2 GO predictions for donkey ENTR1 (A0A8C4MKL2), using human ENTR1 experimental findings, the donkey and human ENTR1 gene reviews, and a donkey-human sequence comparison. The donkey entry (356 aa) conserves the C-terminal coiled-coil region (81% identity to human ENTR1) but lacks the region corresponding to human residues 9-85. Endocytic recycling is a correct process prediction, transferred by orthology from human IMP evidence, that is absent from donkey GOA (COR). Retromer complex is uncertain (UNC), because human ENTR1 associates with retromer indirectly through the WASH complex and colocalizes with it rather than being an established subunit. ProtNLM2 also emitted a non-GO subcellular location ("Membrane") for this accession, which is not scored here.

Source documents: projects/PROTNLM_EVALUATION/donkey40/donkey40-predictions.tsv · genes/EQUAS/ENTR1/ENTR1-uniprot.txt · genes/EQUAS/ENTR1/ENTR1-goa.tsv · genes/EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt · genes/EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md · genes/EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS-rereview.md · genes/EQUAS/ENTR1/ENTR1-ai-review.yaml · genes/human/ENTR1/ENTR1-ai-review.yaml

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0032456 endocytic recycling GO_BP
COR — Correct novel prediction Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: Human ENTR1 (SDCCAG3) was identified in the VPS35 interactome, and its siRNA depletion reduces surface and total GLUT1, an SNX27-retromer recycling cargo, with minor effects on other cargo such as CD97 (PMID:25278552); the human gene review accepts endocytic recycling as an experimentally supported core process, while noting that the effect is cargo-selective and that ENTR1 also promotes lysosomal sorting of Fas (PMID:31308371). Transfer to donkey is an orthology inference, as donkey A0A8C4MKL2 (PTHR31259:SF3) and human ENTR1 (hominid-only SF6) are the single ENTR1 ortholog in each species, and the conserved C-terminal coiled-coil region shares 81% identity. The donkey gene review describes the recycling role in its description and core-function text but does not carry it as a GO annotation, because PAINT did not propagate this human term, and the term is absent from donkey GOA. The prediction is therefore a correct, novel annotation for this accession, with the caveat that it rests on human knockdown data rather than on the donkey protein.
Supporting Evidence:
GO:0030904 retromer complex GO_CC
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: Human ENTR1 co-purifies with VPS35 and colocalizes with the retromer cargo-selective complex on endosomes (PMID:25278552), but its association with retromer is mediated by the WASH complex (PMID:24980502), and the human gene review accepts the retromer term only with the colocalizes_with qualifier, as an accessory association rather than subunit membership. An unqualified retromer complex term implies membership, which no evidence establishes; the indirect, WASH-dependent association argues against a stable subunit role but does not exclude a peripheral one. The prediction is thus plausible as an association but neither supported nor refuted as complex membership. The term is absent from donkey GOA.
Supporting Evidence:
  • file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt: "Colocalizes in a WASHC2-dependent manner with the retromer CSC CC complex at endosomes"
  • PMID:25278552: "This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3)"
  • PMID:24980502: "Together, these data establish that the association of ANKRD50, SDCCAG3, and RME-8 to retromer is mediated through binding to the WASH complex"

Deep Research

Cyberian

(ENTR1-deep-research-cyberian.md)

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📚 Additional Documentation

Notes

(ENTR1-notes.md)

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Bioinformatics Results

(RESULTS.md)

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📄 View Raw YAML

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