id: C9J7I0 gene_symbol: UMAD1 product_type: PROTEIN aliases: - RPA3-AS1 - RPA3OS - UBAP1-MVB12-associated (UMA)-domain containing protein 1 status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- UMAD1 is a poorly characterized 137 amino acid human protein containing a predicted C-terminal UMA domain. Its name and domain architecture place it in the UBAP1/MVB12-associated UMA-domain protein family, but current local evidence does not establish a specific ESCRT-I complex, endosomal sorting, autophagy, membrane fission, or viral budding function for UMAD1. UniProt lists no FUNCTION comment or GO cross-references for UMAD1, and GOA currently contains only broad IntAct protein-binding evidence from a large-scale binary interactome map. references: - id: UniProt:C9J7I0 title: UniProt entry for UMAD1 (C9J7I0) findings: - statement: >- UniProt names the protein "UBAP1-MVB12-associated (UMA)-domain containing protein 1", records a UMA domain, lists interactions with GABARAPL1 and TH isoform 3, and has no GO cross-references or FUNCTION comment for UMAD1. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: >- PMID:32296183 generated the HuRI binary interactome by systematic yeast two-hybrid screening and follow-up verification; it is not a focused UMAD1 functional study. - id: PMID:32424346 title: 'A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.' findings: - statement: >- The paper lists UMAD1 among possible UMA-domain fourth subunits of human ESCRT-I, but the experimental structure and mechanism use other ESCRT-I subunits and the discussion notes that some theoretical complexes may not form. - id: file:human/UMAD1/UMAD1-notes.md title: Local curation notes for UMAD1 findings: - statement: >- Local synthesis found no direct evidence supporting UMAD1 as an established ESCRT-I subunit or proteostasis-pathway effector. - id: file:human/UMAD1/UMAD1-deep-research-falcon.md title: Falcon deep research report for UMAD1 findings: - statement: >- The Falcon report asserts that UMAD1 is a cytokinesis-specialized ESCRT-I subunit that pairs with VPS37C/VPS37B, stabilizes the CEP55-TSG101 interaction at the midbody, and facilitates ESCRT-III dynamic subunit turnover during abscission, with partial functional redundancy with ALIX. Nearly all of these specific claims trace to a single primary source (Glover et al. 2023, J Cell Sci, doi:10.1242/jcs.261097) that is NOT present in the local publications cache and could not be verified here. - statement: >- The report itself notes that direct experimental demonstration of UMAD1-specific roles in endosomal cargo sorting, autophagosome closure, or membrane repair remains an open area, and that the STING-degradation evidence it cites is for UBAP1 rather than UMAD1. These broader ESCRT roles are therefore inferences by family analogy, not UMAD1-specific data. reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: >- Relevance is MEDIUM because the report plausibly identifies the relevant biological context (UMA-domain ESCRT-I accessory subunit family) and a primary functional study (Glover et al. 2023) that, if verified, would substantially inform UMAD1 function. Correctness is UNVERIFIED: the strong claims ("Primary Function: Role in Cytokinetic Abscission" and "Functional Redundancy with ALIX") rest almost entirely on the Glover 2023 paper, which is not in the local cache and was not read; the report's per-claim "citations" are page-range tags rather than checkable quotes. The well-supported, cross-checkable elements are the family/architecture statements that agree with the locally cached Flower 2020 paper (PMID:32424346) and UniProt (UMA domain, MVB12-like position in human ESCRT-I; "some theoretical complexes may not form"). The abscission, CEP55/TSG101-stabilization, ESCRT-III-turnover, and ALIX-redundancy claims should be treated as DISPUTED/unverified pending direct reading of Glover 2023, and were NOT promoted into accepted GO functions, core_functions, or the description in this review. existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- This annotation comes from IntAct records based on the HuRI human binary interactome map, with UMAD1 interactions to TH isoform 3 and GABARAPL1 present in the local UniProt record. The interaction-screen evidence supports that UMAD1 can score in binary protein-interaction assays, but the GO term "protein binding" is too generic to represent a meaningful molecular function, and the partners do not establish a coherent UMAD1 core role. action: MARK_AS_OVER_ANNOTATED reason: >- Generic protein binding is discouraged because it does not describe the actual activity or pathway role of the gene product. Here, the evidence is a large-scale interactome screen rather than a targeted functional study, and no more specific UMAD1 molecular function can be assigned from the local evidence. The Falcon deep research report proposes a specific ESCRT-I-adaptor molecular function for UMAD1 (selective binding to TSG101, VPS28, and VPS37C/VPS37B via a VPF motif), but that proposal derives from a single uncached primary study (Glover et al. 2023) that could not be verified here, and the report itself concedes that several UMAD1-specific roles "remains an important area for future investigation." This does not provide a verifiable basis to replace the generic protein-binding term, so the over-annotation call is retained. supported_by: - reference_id: UniProt:C9J7I0 supporting_text: "CC C9J7I0; Q9H0R8: GABARAPL1; NbExp=3; IntAct=EBI-10989060, EBI-746969;" - reference_id: UniProt:C9J7I0 supporting_text: "CC C9J7I0; P07101-3: TH; NbExp=3; IntAct=EBI-10989060, EBI-12001016;" - reference_id: PMID:32296183 supporting_text: "To map the reference interactome, we performed nine screens of Space III, followed by pairwise verification by quadruplicate retesting and sequence confirmation." - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: "The existing `GO:0005515 protein binding` annotation is supported as a broad interaction-screen observation, but it is uninformative as a molecular function and should be marked as over-annotated." - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: "though direct experimental demonstration of UMAD1-specific roles in endosomal cargo sorting, autophagosome closure, or membrane repair remains an important area for future investigation." core_functions: - description: >- Molecular function unknown for this poorly characterized UMA-domain protein; no direct evidence reviewed here supports a specific ESCRT-I, endosomal sorting, autophagy, membrane fission, or viral budding function for UMAD1. A Falcon deep research report proposes that UMAD1 is a cytokinesis-specialized ESCRT-I accessory subunit (pairing with TSG101/VPS28/VPS37C and acting at the midbody), but this rests on a single primary study (Glover et al. 2023) that is not in the local cache and could not be verified, so no core function is assigned here. supported_by: - reference_id: UniProt:C9J7I0 supporting_text: "DR PAN-GO; C9J7I0; 0 GO annotations based on evolutionary models." - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: "No core GO function is assigned in this review." - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: "As an ESCRT-I component, UMAD1 is positioned to contribute to these processes, though specific roles beyond cytokinesis remain to be experimentally demonstrated." proposed_new_terms: [] suggested_questions: - question: >- Does endogenous UMAD1 assemble with TSG101, VPS28, and any VPS37 paralog into a stable ESCRT-I complex in human cells? - question: >- If UMAD1 forms an ESCRT-I variant, what cargoes, membranes, or tissues require the UMAD1-containing complex rather than MVB12A, MVB12B, or UBAP1 variants? - question: >- Are the HuRI interactions with GABARAPL1 or TH isoform 3 reproducible at endogenous expression levels and relevant to a cellular process? suggested_experiments: - description: >- Perform endogenous tagging or validated-antibody co-immunoprecipitation of UMAD1 followed by targeted immunoblotting or mass spectrometry for TSG101, VPS28, VPS37 paralogs, MVB12A, MVB12B, and UBAP1. hypothesis: >- UMAD1 may assemble into a specific ESCRT-I variant, but this must be shown directly before ESCRT-I complex annotations are justified. - description: >- Use CRISPR knockout or acute depletion of UMAD1 with assays for ubiquitinated cargo sorting, intralumenal vesicle formation, and endosome morphology. hypothesis: >- If UMAD1 is a functional ESCRT-I fourth subunit, loss of UMAD1 should cause a measurable defect in at least one ESCRT-dependent endosomal sorting workflow. - description: >- Validate the HuRI GABARAPL1 and TH isoform 3 interactions with reciprocal co-immunoprecipitation or purified-protein binding assays. hypothesis: >- The binary-interactome partners may be reproducible physical interactors, but they do not yet define UMAD1 molecular function. knowledge_gaps: - gap_statement: >- It is unresolved whether endogenous UMAD1 assembles into a stable human ESCRT-I complex, and if so which TSG101/VPS28/VPS37-containing complex it joins and what molecular role its UMA domain performs. boundary: >- UMAD1 has a predicted UMA domain and is listed by Flower et al. 2020 among possible UMA-domain fourth subunits of human ESCRT-I. Local evidence does not verify a UMAD1-containing ESCRT-I complex, and the only GOA evidence is broad HuRI protein binding to GABARAPL1 and TH isoform 3. gap_kind: - BIOLOGY - CURATION dark_aspect: MF_DARK status: OPEN significance: >- ESCRT-I complex membership would be the key molecular anchor for all more specific UMAD1 process annotations. Without direct assembly evidence, adding ESCRT-I, membrane-fission, ubiquitin-binding, or adaptor-function terms would overstate the local evidence. resolution: >- Endogenous UMAD1 tagging or validated-antibody immunoprecipitation with TSG101, VPS28, VPS37 paralogs, MVB12A/B, UBAP1, and ALIX, plus purified UMA-domain binding assays and motif mutants, would establish whether UMAD1 is an ESCRT-I subunit and define its molecular partners. provenance: - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: UMAD1 should be treated as a poorly characterized UMA-domain protein rather than as an experimentally established ESCRT-I subunit in this review. - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: The name and domain architecture make ESCRT-I membership plausible, and the proteostasis network entry is useful search context, but the local evidence does not show UMAD1 incorporation into an ESCRT-I complex - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: No core GO function is assigned in this review. - gap_statement: >- The biological process in which UMAD1 acts is unresolved. Cytokinetic abscission is proposed by an uncached 2023 primary study summarized in Falcon deep research, while endosomal sorting, autophagosome closure, membrane repair, and viral budding remain family-level ESCRT inferences rather than locally verified UMAD1 functions. boundary: >- The Falcon report identifies a potentially decisive Glover et al. 2023 cytokinesis paper, but that paper is not in the local cache and was not read for this review. The locally cached Flower et al. paper supports UMA-domain ESCRT-I architectural context but does not establish a UMAD1-specific process. gap_kind: - BIOLOGY - CURATION dark_aspect: BP_DARK status: OPEN significance: >- UMAD1 currently cannot be assigned a defensible biological-process term beyond treating protein-binding evidence as over-annotated. Resolving this gap would determine whether UMAD1 belongs in cytokinesis, endosomal MVB sorting, autophagy, membrane repair, or no currently supported ESCRT-dependent process. resolution: >- Cache and review the Glover et al. 2023 article, verify its UMAD1-specific supporting text, then test UMAD1 perturbation in cytokinetic abscission, endosomal cargo sorting, autophagosome closure, and membrane repair assays with rescue by wild-type and ESCRT-binding-defective UMAD1. provenance: - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: though direct experimental demonstration of UMAD1-specific roles in endosomal cargo sorting, autophagosome closure, or membrane repair remains an important area for future investigation. - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: As an ESCRT-I component, UMAD1 is positioned to contribute to these processes, though specific roles beyond cytokinesis remain to be experimentally demonstrated. - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: Adding ESCRT-I complex membership, MVB sorting, ubiquitin binding, phospholipid binding, membrane fission, or macroautophagy terms would overstate the available evidence. - gap_statement: >- The compartment where UMAD1 acts is unresolved. Midbody localization is asserted in the unverified cytokinesis model, while endosomal localization is inferred from ESCRT-I family context; neither compartment is established from locally reviewed endogenous UMAD1 evidence. boundary: >- UMAD1's domain architecture places it among UMA-domain ESCRT-I-associated proteins, and the Falcon report describes context-dependent midbody and expected endosomal localization. The local review does not accept those locations as established cellular-component annotations. gap_kind: - BIOLOGY - CURATION dark_aspect: CC_DARK status: OPEN significance: >- Distinguishing midbody, endosomal, autophagosome-associated, or other pools is essential for deciding whether UMAD1 should receive ESCRT-I complex, midbody, endosome, or autophagy-related location annotations. resolution: >- Use endogenous tagging or validated antibodies for UMAD1 localization through the cell cycle and during ESCRT-dependent endosomal/autophagy perturbations, paired with CEP55, TSG101, VPS37, ALIX, endosome, and autophagosome markers. provenance: - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: While direct endosomal localization of UMAD1 has not been extensively documented in the available literature - reference_id: file:human/UMAD1/UMAD1-notes.md supporting_text: the local evidence does not show UMAD1 incorporation into an ESCRT-I complex, endosomal cargo sorting, membrane fission, autophagy, or viral budding. - reference_id: file:human/UMAD1/UMAD1-deep-research-falcon.md supporting_text: UMAD1 exhibits context-dependent subcellular localization.