CHMP3

id: Q9Y3E7
gene_symbol: CHMP3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CHMP3 (also known as VPS24/hVps24) is a core component of the ESCRT-III complex,
  belonging to the SNF7 protein family. It functions as a non-enzymatic structural
  subunit that co-polymerizes with CHMP2A and CHMP4B to form helical/spiral
  polymers that constrict and sever membrane necks in "reverse topology"
  membrane fission events (budding away from the cytosol). CHMP3 is maintained
  in an autoinhibited cytosolic state and is activated upon recruitment to
  membranes through interaction with other ESCRT-III components. The VPS4 AAA+
  ATPase disassembles CHMP3-containing polymers after membrane scission. CHMP3
  participates in multivesicular body (MVB) formation and cargo sorting to
  lysosomes, cytokinetic abscission at the midbody, nuclear envelope reformation
  during telophase, plasma membrane repair, and is hijacked by enveloped viruses
  (notably HIV-1) for budding. It also plays roles in autophagosome maturation
  and endosomal proteostasis relevant to neurodegenerative disease.

core_functions:
  - molecular_function:
      id: GO:0005515
      label: protein binding
    description: >-
      CHMP3 is a core structural component of the ESCRT-III complex. It forms
      helical copolymers with CHMP2A that can be disassembled by VPS4 ATPase
      (PMID:18687924). Crystal structure solved (PDB 3FRT). The minimal human
      ESCRT-III scission module includes CHMP2A, CHMP3, CHMP4B with VPS4B.
    in_complex:
      id: GO:0000815
      label: ESCRT III complex
    directly_involved_in:
      - id: GO:0090148
        label: membrane fission
    locations:
      - id: GO:0005771
        label: multivesicular body
      - id: GO:0031902
        label: late endosome membrane
    supported_by:
      - reference_id: PMID:18687924
        supporting_text: "CHMP2A and CHMP3 copolymerized in solution, and their membrane
          targeting was cooperatively enhanced on planar lipid bilayers."

  - molecular_function:
      id: GO:0180020
      label: membrane bending activity
    description: >-
      CHMP3 participates in ESCRT-III-mediated membrane fission across multiple
      cellular contexts. The ESCRT-III proteins CHMP2A and CHMP3 assemble into
      helical tubular structures that expose membrane interaction sites on the
      outside and can catalyze late steps in membrane budding (PMID:18687924).
    in_complex:
      id: GO:0000815
      label: ESCRT III complex
    directly_involved_in:
      - id: GO:0071985
        label: multivesicular body sorting pathway
    locations:
      - id: GO:0032585
        label: multivesicular body membrane
    supported_by:
      - reference_id: PMID:18687924
        supporting_text: "We found that the ESCRT-III proteins CHMP2A and CHMP3...could
          assemble in vitro into helical tubular structures that expose their membrane
          interaction sites on the outside of the tubule"

  - molecular_function:
      id: GO:0005515
      label: protein binding
    description: >-
      CHMP3/hVps24 is required for degradation of EGFR and transport from early
      endosomes to lysosomes. Depletion causes accumulation of EGFRs in small
      MVEs with impaired fusion to lysosomes (PMID:16554368).
    in_complex:
      id: GO:0000815
      label: ESCRT III complex
    directly_involved_in:
      - id: GO:0061952
        label: midbody abscission
    locations:
      - id: GO:0030496
        label: midbody
    supported_by:
      - reference_id: PMID:20616062
        supporting_text: "depletion of VPS4A, VPS4B, or any of the 11 different human
          ESCRT-III (CHMP) proteins inhibited abscission"

  - molecular_function:
      id: GO:0005515
      label: protein binding
    description: >-
      CHMP3 is part of the minimal ESCRT-III set hijacked by HIV-1 for budding
      (CHMP2A, CHMP3, CHMP4B, VPS4B). Dominant-negative CHMP3 mutants arrest
      HIV-1 budding. CHMP3 overexpression strongly inhibits HIV-1 release.
    in_complex:
      id: GO:0000815
      label: ESCRT III complex
    directly_involved_in:
      - id: GO:0039702
        label: viral budding via host ESCRT complex
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: PMID:14505570
        supporting_text: "dominant-negative mutants of late-acting human class E proteins
          arrested HIV-1 budding"

existing_annotations:
# IBA annotations from phylogenetic inference
  - term:
      id: GO:0005771
      label: multivesicular body
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHMP3/VPS24 is a core ESCRT-III subunit that functions at MVBs to mediate
        ILV formation. IBA annotation is phylogenetically sound as Vps24 function
        at MVBs is conserved from yeast.
      action: ACCEPT
      reason: >-
        CHMP3 localization to MVBs is well-supported. Bache et al. (PMID:16554368)
        showed endogenous hVps24 localized mainly to late endosomes and MVBs.
        The deep research confirms CHMP3 acts at endosomal limiting membranes
        for ILV formation.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Like Tsg101, endogenous hVps24 localized mainly to late
            endosomes."

        - reference_id: file:human/CHMP3/CHMP3-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0015031
      label: protein transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHMP3 participates in protein transport as part of ESCRT-III mediated
        cargo sorting to lysosomes.
      action: ACCEPT
      reason: >-
        While general, this term is appropriate as CHMP3 is required for transport
        of cargo proteins like EGFR from endosomes to lysosomes (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Depletion of hVps24 by siRNA showed that this ESCRT subunit,
            like Tsg101, is important for degradation of the epidermal growth factor
            (EGF) receptor (EGFR) and for transport of the receptor from early endosomes
            to lysosomes."

  - term:
      id: GO:0032509
      label: endosome transport via multivesicular body sorting pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHMP3 is essential for MVB-mediated endosomal transport as a core ESCRT-III
        component.
      action: ACCEPT
      reason: >-
        This is a core function of CHMP3. The MVB sorting pathway requires
        ESCRT-III for ILV formation and cargo sorting.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "hVps24 is required for degradation but not silencing of
            the epidermal growth factor receptor"

  - term:
      id: GO:0045324
      label: late endosome to vacuole transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHMP3 is required for late endosome to lysosome transport (vacuole is the
        yeast equivalent of lysosome).
      action: ACCEPT
      reason: >-
        Conserved function from yeast Vps24. In human cells, CHMP3 is required
        for transport from late endosomes to lysosomes.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Electron microscopy of hVps24-depleted cells showed an
            accumulation of EGFRs in MVEs that were significantly smaller than those
            in control cells, probably because of an impaired fusion with lyso-bisphosphatidic
            acid-positive late endosomes/lysosomes."

  - term:
      id: GO:0000815
      label: ESCRT III complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHMP3 is a core structural subunit of the ESCRT-III complex. This is one
        of the most fundamental aspects of CHMP3 function.
      action: ACCEPT
      reason: >-
        CHMP3/VPS24 is unambiguously a core ESCRT-III component, demonstrated by
        structural studies showing CHMP2A-CHMP3 helical copolymers (PMID:18687924)
        and functional studies.
      supported_by:
        - reference_id: PMID:18687924
          supporting_text: "CHMP2A and CHMP3 copolymerized in solution, and their
            membrane targeting was cooperatively enhanced on planar lipid bilayers."

# IEA annotations
  - term:
      id: GO:0000776
      label: kinetochore
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        IEA annotation suggesting CHMP3 localizes to kinetochores. This is
        supported by a global screen (PMID reference in later IDA annotation).
      action: ACCEPT
      reason: >-
        CHMP3 was reported to localize to kinetochores in a global screen for
        proteins with mitotic functions (cited in PMID:20616062). While not a
        primary localization, it appears to be a real secondary site.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "CHMP3 and CHMP4, were recently reported to localize to
            kinetochores in a global screen for proteins with possible mitotic functions"

  - term:
      id: GO:0001778
      label: plasma membrane repair
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ESCRT machinery including CHMP3 is required for plasma membrane repair.
      action: ACCEPT
      reason: >-
        Supported by direct evidence (PMID:24482116) showing ESCRT machinery is
        required for plasma membrane repair. The IEA correctly captures this
        established ESCRT-III function.
      supported_by:
        - reference_id: PMID:24482116
          supporting_text: "ESCRT machinery is required for plasma membrane repair"

  - term:
      id: GO:0005643
      label: nuclear pore
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        IEA suggesting CHMP3 localizes to nuclear pores. While ESCRT-III acts at
        the nuclear envelope during reformation, nuclear pore localization
        specifically is less well established for CHMP3.
      action: KEEP_AS_NON_CORE
      reason: >-
        ESCRT-III (particularly CHMP2A) localizes to nucleo-cytoplasmic channels
        during NE reformation (PMID:26040713), which are distinct from nuclear
        pores. However, proximity to NE fenestrations may be captured by this
        term. Not a core localization.
      supported_by:
        - reference_id: PMID:26040713
          supporting_text: "On these sheets, CHMP2A localised to discrete regions,
            with intact NE being devoid of label, but with CHMP2A preferentially...decorating
            nucleo-cytoplasmic channels"

  - term:
      id: GO:0005765
      label: lysosomal membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 may transiently associate with lysosomal membranes during
        ESCRT-dependent processes.
      action: ACCEPT
      reason: >-
        ESCRT-III is implicated in lysosomal microautophagy and MVB-lysosome
        fusion processes. Experimental evidence (IDA, PMID:17984323) supports
        lysosomal membrane localization.
      supported_by:
        - reference_id: PMID:17984323
          supporting_text: "Functional multivesicular bodies are required for autophagic
            clearance"

  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHMP3 localizes to endosomes as part of ESCRT-III function in MVB
        biogenesis.
      action: ACCEPT
      reason: >-
        Well-established localization. CHMP3/hVps24 localizes mainly to late
        endosomes and functions in endosomal sorting (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Like Tsg101, endogenous hVps24 localized mainly to late
            endosomes."

  - term:
      id: GO:0005828
      label: kinetochore microtubule
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        IEA annotation for kinetochore microtubule localization of CHMP3.
      action: KEEP_AS_NON_CORE
      reason: >-
        While CHMP3 has been found at kinetochores in screens (PMID:20616062),
        kinetochore microtubule localization specifically is less directly
        supported. This is secondary to core ESCRT-III functions.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "CHMP3 and CHMP4, were recently reported to localize to
            kinetochores in a global screen"

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHMP3 exists in an autoinhibited form in the cytosol before membrane
        recruitment.
      action: ACCEPT
      reason: >-
        ESCRT-III subunits including CHMP3 are cytosolic in their autoinhibited
        form and are recruited to membranes upon activation. This is well
        established from structural and biochemical studies.
      supported_by:
        - reference_id: PMID:18395747
          supporting_text: "Structural basis for autoinhibition of ESCRT-III CHMP3"

  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation linking CHMP3 to apoptosis. Isoform 2 of CHMP3 can prevent
        stress-mediated cell death in yeast.
      action: KEEP_AS_NON_CORE
      reason: >-
        UniProt notes that Isoform 2 prevents stress-mediated cell death in yeast.
        This is a secondary function not representing core ESCRT-III activity.
        May reflect indirect effects of ESCRT dysfunction.
  - term:
      id: GO:0007034
      label: vacuolar transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHMP3/VPS24 functions in vacuolar transport (vacuole being the yeast
        equivalent of lysosome).
      action: ACCEPT
      reason: >-
        This reflects the conserved function of Vps24 in vacuolar protein sorting.
        InterPro domain mapping correctly identifies this core function.

  - term:
      id: GO:0015031
      label: protein transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Duplicate of IBA annotation. CHMP3 functions in protein transport via
        ESCRT-III.
      action: ACCEPT
      reason: >-
        Same as IBA annotation - CHMP3 is required for protein transport to
        lysosomes as part of ESCRT-III function.

  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHMP3 associates with membranes during ESCRT-III function.
      action: ACCEPT
      reason: >-
        While very general, this is accurate. CHMP3 is recruited to membranes
        where it polymerizes to effect membrane scission.

  - term:
      id: GO:0031902
      label: late endosome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHMP3 localizes to late endosome membranes as part of ESCRT-III function.
      action: ACCEPT
      reason: >-
        Well-supported. Bache et al. showed endogenous hVps24 localized mainly
        to late endosomes (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Like Tsg101, endogenous hVps24 localized mainly to late
            endosomes."

  - term:
      id: GO:0032585
      label: multivesicular body membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 localizes to MVB membranes where it functions in ILV formation.
      action: ACCEPT
      reason: >-
        Core localization for ESCRT-III function in MVB biogenesis. Supported
        by direct evidence (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Electron microscopy of hVps24-depleted cells showed an
            accumulation of EGFRs in MVEs"

  - term:
      id: GO:0039702
      label: viral budding via host ESCRT complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 is part of the ESCRT machinery hijacked by enveloped viruses for
        budding.
      action: ACCEPT
      reason: >-
        Well-established core function. CHMP3 is part of the minimal ESCRT-III
        set for HIV-1 budding (PMID:14505570, PMID:16740483).
      supported_by:
        - reference_id: PMID:14505570
          supporting_text: "dominant-negative mutants of late-acting human class E
            proteins arrested HIV-1 budding"

  - term:
      id: GO:0043162
      label: ubiquitin-dependent protein catabolic process via the 
        multivesicular body sorting pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 functions in ubiquitin-dependent cargo sorting to MVBs.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function. Ubiquitinated cargo like EGFR and alpha-synuclein
        require ESCRT-III including CHMP3 for lysosomal degradation.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "ESCRT-I, -II, and -III, are thought to mediate the biogenesis
            of multivesicular endosomes (MVEs) and endosomal sorting of ubiquitinated
            membrane proteins"

  - term:
      id: GO:0046761
      label: viral budding from plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 functions in viral budding from plasma membrane as part of
        ESCRT-III.
      action: ACCEPT
      reason: >-
        HIV-1 buds from the plasma membrane using ESCRT machinery. CHMP3 is
        part of the minimal scission set for HIV-1 budding.
      supported_by:
        - reference_id: PMID:16740483
          supporting_text: "Structural basis for budding by the ESCRT-III factor CHMP3"

  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CHMP3 functions in cell division via its role in cytokinetic abscission
        and centrosome maintenance.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for cytokinetic abscission. Depletion of any CHMP
        protein inhibits abscission (PMID:20616062).
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "depletion of VPS4A, VPS4B, or any of the 11 different
            human ESCRT-III (CHMP) proteins inhibited abscission"

  - term:
      id: GO:0061952
      label: midbody abscission
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 is required for midbody abscission during cytokinesis.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function. Systematic analysis showed CHMP3 depletion
        inhibits abscission (PMID:20616062).
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "depletion of VPS4A, VPS4B, or any of the 11 different
            human ESCRT-III (CHMP) proteins inhibited abscission"

  - term:
      id: GO:0071985
      label: multivesicular body sorting pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 functions in the MVB sorting pathway as a core ESCRT-III component.
      action: ACCEPT
      reason: >-
        Core function. CHMP3/hVps24 is required for MVB-mediated receptor
        degradation (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "The ESCRT-III subunit hVps24 is required for degradation
            but not silencing of the epidermal growth factor receptor"

  - term:
      id: GO:0097352
      label: autophagosome maturation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ESCRT-III including CHMP3 is required for autophagosome maturation.
      action: ACCEPT
      reason: >-
        Supported by experimental evidence showing functional MVBs are required
        for autophagic clearance (PMID:17984323).
      supported_by:
        - reference_id: PMID:17984323
          supporting_text: "Functional multivesicular bodies are required for autophagic
            clearance of protein aggregates"

  - term:
      id: GO:1902774
      label: late endosome to lysosome transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 is required for late endosome to lysosome transport.
      action: ACCEPT
      reason: >-
        CHMP3 depletion impairs MVB-lysosome fusion and EGFR degradation
        (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "hVps24 depletion results in the accumulation of EGFRs
            in small endosomes... probably because of an impaired fusion with lyso-bisphosphatidic
            acid-positive late endosomes/lysosomes"

  - term:
      id: GO:1904930
      label: amphisome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHMP3 localizes to amphisome membranes during autophagy.
      action: ACCEPT
      reason: >-
        Amphisomes are intermediates in autophagy formed by fusion of
        autophagosomes with endosomes. ESCRT-III function is required for
        autophagy (PMID:17984323).

  - term:
      id: GO:0005546
      label: phosphatidylinositol-4,5-bisphosphate binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for PI(4,5)P2 binding by CHMP3.
      action: MODIFY
      reason: >-
        UniProt indicates CHMP3 selectively binds PI(3,5)P2 and PI(3,4)P2 in
        preference to other phosphoinositides. PI(4,5)P2 binding is less specific.
        The annotation should be more accurate to the tested lipid preferences.
      proposed_replacement_terms:
        - id: GO:0080025
          label: phosphatidylinositol-3,5-bisphosphate binding

  - term:
      id: GO:0005769
      label: early endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CHMP3 can be found on early endosomes, though predominantly on late
        endosomes.
      action: ACCEPT
      reason: >-
        Bache et al. note that while bulk hVps24 is on late endosomes, some
        EEA1-positive early endosomes do contain hVps24 (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "we did observe a few EEA1-positive structures that labeled
            for endogenous hVps24"

  - term:
      id: GO:0005770
      label: late endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CHMP3 localizes predominantly to late endosomes.
      action: ACCEPT
      reason: >-
        Primary localization site for CHMP3/hVps24 (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Like Tsg101, endogenous hVps24 localized mainly to late
            endosomes."

  - term:
      id: GO:0008333
      label: endosome to lysosome transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CHMP3 is required for endosome to lysosome transport.
      action: ACCEPT
      reason: >-
        Core function of CHMP3/hVps24 in ESCRT-III-mediated cargo trafficking
        (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Depletion of hVps24 by siRNA showed that this ESCRT subunit,
            like Tsg101, is important for degradation of the epidermal growth factor
            (EGF) receptor (EGFR) and for transport of the receptor from early endosomes
            to lysosomes"

  - term:
      id: GO:0030496
      label: midbody
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CHMP3 localizes to the midbody during cytokinesis.
      action: ACCEPT
      reason: >-
        ESCRT-III proteins localize to the midbody for abscission. Supported
        by direct evidence (PMID:20616062, PMID:26040712).
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "VPS4 proteins concentrated at spindle poles during mitosis
            and then at midbodies during cytokinesis"

  - term:
      id: GO:0032467
      label: positive regulation of cytokinesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CHMP3 positively regulates cytokinesis through its role in abscission.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for cytokinesis. Depletion inhibits abscission
        (PMID:20616062).
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "depletion of VPS4A, VPS4B, or any of the 11 different
            human ESCRT-III (CHMP) proteins inhibited abscission"

  - term:
      id: GO:0051036
      label: regulation of endosome size
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        CHMP3 depletion affects endosome size.
      action: ACCEPT
      reason: >-
        hVps24 depletion causes accumulation of EGFRs in MVEs that are
        significantly smaller than control (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Electron microscopy of hVps24-depleted cells showed an
            accumulation of EGFRs in MVEs that were significantly smaller than those
            in control cells"

# IDA/IMP/other experimental annotations
  - term:
      id: GO:0090148
      label: membrane fission
    evidence_type: IDA
    original_reference_id: PMID:36604498
    review:
      summary: >-
        Direct experimental evidence for CHMP3 role in membrane fission.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function. CHMP3 co-polymerizes with CHMP2A to drive
        membrane scission.

      supported_by:
        - reference_id: PMID:36604498
          supporting_text: Epub 2023 Jan 5. Structural basis of CHMP2A-CHMP3 
            ESCRT-III polymer assembly and membrane cleavage.
  - term:
      id: GO:0180020
      label: membrane bending activity
    evidence_type: IDA
    original_reference_id: PMID:36604498
    review:
      summary: >-
        CHMP3 contributes to membrane bending as part of ESCRT-III polymers.
      action: ACCEPT
      reason: >-
        ESCRT-III polymers bend and constrict membranes. The helical CHMP2A-CHMP3
        structures can deform membranes (PMID:18687924).
      supported_by:
        - reference_id: PMID:18687924
          supporting_text: "We found that the ESCRT-III proteins CHMP2A and CHMP3...could
            assemble in vitro into helical tubular structures that expose their membrane
            interaction sites on the outside of the tubule"

        - reference_id: PMID:36604498
          supporting_text: Epub 2023 Jan 5. Structural basis of CHMP2A-CHMP3 
            ESCRT-III polymer assembly and membrane cleavage.
  - term:
      id: GO:0000421
      label: autophagosome membrane
    evidence_type: IDA
    original_reference_id: PMID:17984323
    review:
      summary: >-
        CHMP3 localizes to autophagosome membranes.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for autophagy and autophagic clearance.

      supported_by:
        - reference_id: PMID:17984323
          supporting_text: Functional multivesicular bodies are required for 
            autophagic clearance of protein aggregates associated with 
            neurodegenerative disease.
  - term:
      id: GO:0000776
      label: kinetochore
    evidence_type: IDA
    original_reference_id: PMID:26040712
    review:
      summary: >-
        Direct evidence for CHMP3 localization to kinetochores.
      action: ACCEPT
      reason: >-
        Global screen identified CHMP3 at kinetochores (cited in PMID:20616062).
        Secondary localization related to mitotic functions.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "CHMP3 and CHMP4, were recently reported to localize to
            kinetochores in a global screen for proteins with possible mitotic functions"

        - reference_id: PMID:26040712
          supporting_text: Spastin and ESCRT-III coordinate mitotic spindle 
            disassembly and nuclear envelope sealing.
  - term:
      id: GO:0001778
      label: plasma membrane repair
    evidence_type: IDA
    original_reference_id: PMID:24482116
    review:
      summary: >-
        Direct evidence that ESCRT machinery including CHMP3 is required for
        plasma membrane repair.
      action: ACCEPT
      reason: >-
        ESCRT-III mediates membrane resealing after injury. This is a
        topologically equivalent membrane fusion event to other ESCRT functions.
      supported_by:
        - reference_id: PMID:24482116
          supporting_text: "ESCRT machinery is required for plasma membrane repair"

  - term:
      id: GO:0005765
      label: lysosomal membrane
    evidence_type: IDA
    original_reference_id: PMID:17984323
    review:
      summary: >-
        CHMP3 localizes to lysosomal membranes during autophagy-related processes.
      action: ACCEPT
      reason: >-
        ESCRT-III is involved in autophagosome-lysosome fusion and lysosomal
        microautophagy.

      supported_by:
        - reference_id: PMID:17984323
          supporting_text: Functional multivesicular bodies are required for 
            autophagic clearance of protein aggregates associated with 
            neurodegenerative disease.
  - term:
      id: GO:0005828
      label: kinetochore microtubule
    evidence_type: IDA
    original_reference_id: PMID:26040712
    review:
      summary: >-
        CHMP3 has been found at kinetochore microtubules.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary localization. Related to mitotic functions of ESCRT-III but
        not a core function.

      supported_by:
        - reference_id: PMID:26040712
          supporting_text: Spastin and ESCRT-III coordinate mitotic spindle 
            disassembly and nuclear envelope sealing.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:24878737
    review:
      summary: >-
        CHMP3 localizes to plasma membrane during viral budding.
      action: ACCEPT
      reason: >-
        ESCRT-III spirals form at plasma membrane during HIV-1 budding.
      supported_by:
        - reference_id: PMID:24878737
          supporting_text: "Structure of cellular ESCRT-III spirals and their relationship
            to HIV budding"

  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IMP
    original_reference_id: PMID:17984323
    review:
      summary: >-
        Mutant phenotype evidence for CHMP3 role in autophagy.
      action: ACCEPT
      reason: >-
        Functional MVBs are required for autophagic clearance. ESCRT dysfunction
        impairs autophagy.
      supported_by:
        - reference_id: PMID:17984323
          supporting_text: "Functional multivesicular bodies are required for autophagic
            clearance of protein aggregates"

  - term:
      id: GO:0006997
      label: nucleus organization
    evidence_type: IMP
    original_reference_id: PMID:20616062
    review:
      summary: >-
        CHMP3 depletion causes nuclear morphology defects.
      action: ACCEPT
      reason: >-
        ESCRT-III depletion causes defects in chromosome segregation and nuclear
        morphology (PMID:20616062).
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "causing defects in chromosome segregation and nuclear
            morphology"

  - term:
      id: GO:0006997
      label: nucleus organization
    evidence_type: IMP
    original_reference_id: PMID:20616062
    negated: true
    review:
      summary: NOT annotation per GOA (UniProt) indicating CHMP3 is not directly
        involved in nucleus organization.
      action: ACCEPT
      reason: GOA includes a NOT qualifier for this term with the same PMID; 
        capture the negative annotation alongside the positive ComplexPortal 
        entry.

      supported_by:
        - reference_id: PMID:20616062
          supporting_text: Human ESCRT-III and VPS4 proteins are required for 
            centrosome and spindle maintenance.
  - term:
      id: GO:0007080
      label: mitotic metaphase chromosome alignment
    evidence_type: IMP
    original_reference_id: PMID:20616062
    review:
      summary: >-
        CHMP3 depletion affects chromosome alignment.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary effect of ESCRT-III depletion on mitotic processes. Related
        to centrosome/spindle maintenance roles.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "causing defects in chromosome segregation"

  - term:
      id: GO:0007080
      label: mitotic metaphase chromosome alignment
    evidence_type: IMP
    original_reference_id: PMID:20616062
    negated: true
    review:
      summary: NOT annotation per GOA (UniProt) indicating CHMP3 is not directly
        involved in mitotic metaphase chromosome alignment.
      action: ACCEPT
      reason: GOA includes a NOT qualifier for this term with the same PMID; 
        capture the negative annotation alongside the positive ComplexPortal 
        entry.

      supported_by:
        - reference_id: PMID:20616062
          supporting_text: Human ESCRT-III and VPS4 proteins are required for 
            centrosome and spindle maintenance.
  - term:
      id: GO:0030496
      label: midbody
    evidence_type: IDA
    original_reference_id: PMID:26040712
    review:
      summary: >-
        Direct evidence for CHMP3 localization to midbody.
      action: ACCEPT
      reason: >-
        ESCRT-III proteins including CHMP3 localize to the midbody during
        cytokinesis to mediate abscission.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "VPS4 proteins concentrated at spindle poles during mitosis
            and then at midbodies during cytokinesis"

        - reference_id: PMID:26040712
          supporting_text: Spastin and ESCRT-III coordinate mitotic spindle 
            disassembly and nuclear envelope sealing.
  - term:
      id: GO:0031468
      label: nuclear membrane reassembly
    evidence_type: IMP
    original_reference_id: PMID:26040713
    review:
      summary: >-
        ESCRT-III including CHMP3 is required for nuclear envelope reformation.
      action: ACCEPT
      reason: >-
        ESCRT-III controls nuclear envelope reformation by sealing holes in
        the forming NE (PMID:26040713). CHMP3 depletion impairs NE integrity.
      supported_by:
        - reference_id: PMID:26040713
          supporting_text: "However, in CHMP2A-, CHMP3- or UFD1-depleted cells, the
            post-mitotic nucleo-cytoplasmic partitioning of GFP-NLS-βGal was reduced...indicating
            that NE integrity was compromised"

  - term:
      id: GO:0032585
      label: multivesicular body membrane
    evidence_type: IDA
    original_reference_id: PMID:16554368
    review:
      summary: >-
        Direct evidence for CHMP3 localization to MVB membranes.
      action: ACCEPT
      reason: >-
        hVps24 localizes to late endosomes/MVBs (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Electron microscopy of hVps24-depleted cells showed an
            accumulation of EGFRs in MVEs"

  - term:
      id: GO:0036258
      label: multivesicular body assembly
    evidence_type: NAS
    original_reference_id: PMID:16505166
    review:
      summary: >-
        CHMP3 functions in MVB assembly as an ESCRT-III component.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function in ILV formation within MVBs.

      supported_by:
        - reference_id: PMID:16505166
          supporting_text: Recycling of ESCRTs by the AAA-ATPase Vps4 is 
            regulated by a conserved VSL region in Vta1.
  - term:
      id: GO:0039702
      label: viral budding via host ESCRT complex
    evidence_type: IDA
    original_reference_id: PMID:24878737
    review:
      summary: >-
        Direct evidence for CHMP3 function in viral budding.
      action: ACCEPT
      reason: >-
        Structural and functional studies show CHMP3 is part of ESCRT-III
        assemblies mediating HIV-1 budding.
      supported_by:
        - reference_id: PMID:24878737
          supporting_text: "Structure of cellular ESCRT-III spirals and their relationship
            to HIV budding"

  - term:
      id: GO:0043162
      label: ubiquitin-dependent protein catabolic process via the 
        multivesicular body sorting pathway
    evidence_type: IDA
    original_reference_id: PMID:17984323
    review:
      summary: >-
        CHMP3 functions in ubiquitin-dependent cargo degradation via MVBs.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for sorting ubiquitinated cargo to lysosomes.
        This is a core ESCRT-III function.

      supported_by:
        - reference_id: PMID:17984323
          supporting_text: Functional multivesicular bodies are required for 
            autophagic clearance of protein aggregates associated with 
            neurodegenerative disease.
  - term:
      id: GO:0046761
      label: viral budding from plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:24878737
    review:
      summary: >-
        Direct evidence for CHMP3 role in viral budding from plasma membrane.
      action: ACCEPT
      reason: >-
        HIV-1 buds from plasma membrane using ESCRT-III machinery including
        CHMP3.

      supported_by:
        - reference_id: PMID:24878737
          supporting_text: Structure of cellular ESCRT-III spirals and their 
            relationship to HIV budding.
  - term:
      id: GO:0051469
      label: vesicle fusion with vacuole
    evidence_type: NAS
    original_reference_id: PMID:16505166
    review:
      summary: >-
        CHMP3 may function in vesicle fusion with vacuole (lysosome).
      action: ACCEPT
      reason: >-
        MVB-lysosome fusion is impaired upon hVps24 depletion (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "impaired fusion with lyso-bisphosphatidic acid-positive
            late endosomes/lysosomes"

        - reference_id: PMID:16505166
          supporting_text: Recycling of ESCRTs by the AAA-ATPase Vps4 is 
            regulated by a conserved VSL region in Vta1.
  - term:
      id: GO:0061763
      label: multivesicular body-lysosome fusion
    evidence_type: NAS
    original_reference_id: PMID:16505166
    review:
      summary: >-
        CHMP3 is required for MVB-lysosome fusion.
      action: ACCEPT
      reason: >-
        hVps24 depletion causes accumulation of MVBs with impaired lysosome
        fusion (PMID:16554368).
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "impaired fusion with lyso-bisphosphatidic acid-positive
            late endosomes/lysosomes"

        - reference_id: PMID:16505166
          supporting_text: Recycling of ESCRTs by the AAA-ATPase Vps4 is 
            regulated by a conserved VSL region in Vta1.
  - term:
      id: GO:0061952
      label: midbody abscission
    evidence_type: IMP
    original_reference_id: PMID:20616062
    review:
      summary: >-
        Mutant phenotype evidence for CHMP3 role in midbody abscission.
      action: ACCEPT
      reason: >-
        Systematic analysis showed CHMP3 depletion inhibits abscission.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "depletion of VPS4A, VPS4B, or any of the 11 different
            human ESCRT-III (CHMP) proteins inhibited abscission"

  - term:
      id: GO:0071985
      label: multivesicular body sorting pathway
    evidence_type: IDA
    original_reference_id: PMID:16554368
    review:
      summary: >-
        Direct evidence for CHMP3 function in MVB sorting pathway.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function demonstrated by hVps24 depletion studies.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "The ESCRT-III subunit hVps24 is required for degradation"

  - term:
      id: GO:0090148
      label: membrane fission
    evidence_type: NAS
    original_reference_id: PMID:19234443
    review:
      summary: >-
        CHMP3 functions in membrane fission as part of ESCRT-III.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function in membrane scission across multiple contexts.
      supported_by:
        - reference_id: PMID:19234443
          supporting_text: "Membrane scission by the ESCRT-III complex"

  - term:
      id: GO:0097352
      label: autophagosome maturation
    evidence_type: IMP
    original_reference_id: PMID:17984323
    review:
      summary: >-
        ESCRT-III function is required for autophagosome maturation.
      action: ACCEPT
      reason: >-
        Functional MVBs are required for autophagic clearance.
      supported_by:
        - reference_id: PMID:17984323
          supporting_text: "Functional multivesicular bodies are required for autophagic
            clearance"

  - term:
      id: GO:1901673
      label: regulation of mitotic spindle assembly
    evidence_type: IMP
    original_reference_id: PMID:20616062
    review:
      summary: >-
        CHMP3 depletion affects spindle assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary effect of ESCRT-III on centrosome/spindle maintenance.
        Depletion produces multipolar spindles.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "producing multipolar spindles (most ESCRT-III/VPS4 proteins)"

  - term:
      id: GO:1901673
      label: regulation of mitotic spindle assembly
    evidence_type: IMP
    original_reference_id: PMID:20616062
    negated: true
    review:
      summary: NOT annotation per GOA (UniProt) indicating CHMP3 is not directly
        involved in regulation of mitotic spindle assembly.
      action: ACCEPT
      reason: GOA includes a NOT qualifier for this term with the same PMID; 
        capture the negative annotation alongside the positive ComplexPortal 
        entry.

      supported_by:
        - reference_id: PMID:20616062
          supporting_text: Human ESCRT-III and VPS4 proteins are required for 
            centrosome and spindle maintenance.
  - term:
      id: GO:1902774
      label: late endosome to lysosome transport
    evidence_type: IMP
    original_reference_id: PMID:17984323
    review:
      summary: >-
        CHMP3 is required for late endosome to lysosome transport.
      action: ACCEPT
      reason: >-
        Core function. hVps24 depletion impairs MVB-lysosome fusion.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "impaired fusion with lyso-bisphosphatidic acid-positive
            late endosomes/lysosomes"

        - reference_id: PMID:17984323
          supporting_text: Functional multivesicular bodies are required for 
            autophagic clearance of protein aggregates associated with 
            neurodegenerative disease.
  - term:
      id: GO:1904930
      label: amphisome membrane
    evidence_type: IDA
    original_reference_id: PMID:17984323
    review:
      summary: >-
        CHMP3 localizes to amphisome membranes.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for autophagy which involves amphisome formation.

      supported_by:
        - reference_id: PMID:17984323
          supporting_text: Functional multivesicular bodies are required for 
            autophagic clearance of protein aggregates associated with 
            neurodegenerative disease.
  - term:
      id: GO:0140678
      label: molecular function inhibitor activity
    evidence_type: EXP
    original_reference_id: PMID:21827950
    review:
      summary: >-
        CHMP3 has been annotated with molecular function inhibitor activity based
        on its recruitment of AMSH (STAMBP) which acts as a deubiquitinase.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This term is too general and does not capture the specific biological
        role. CHMP3 recruits AMSH/STAMBP which has deubiquitinase activity, but
        CHMP3 itself is not an inhibitor. The structural interaction is better
        described by specific protein binding terms.
      supported_by:
        - reference_id: PMID:21827950
          supporting_text: "Structural basis for ESCRT-III CHMP3 recruitment of AMSH"

  - term:
      id: GO:0046761
      label: viral budding from plasma membrane
    evidence_type: IMP
    original_reference_id: PMID:14505570
    review:
      summary: >-
        Mutant phenotype evidence for CHMP3 role in viral budding.
      action: ACCEPT
      reason: >-
        Dominant-negative CHMP mutants arrest HIV-1 budding.
      supported_by:
        - reference_id: PMID:14505570
          supporting_text: "dominant-negative mutants of late-acting human class E
            proteins arrested HIV-1 budding"

  - term:
      id: GO:0000815
      label: ESCRT III complex
    evidence_type: IDA
    original_reference_id: PMID:18687924
    review:
      summary: >-
        Direct structural evidence for CHMP3 as ESCRT-III component.
      action: ACCEPT
      reason: >-
        Crystal structures and EM show CHMP2A-CHMP3 helical copolymers.
      supported_by:
        - reference_id: PMID:18687924
          supporting_text: "We found that the ESCRT-III proteins CHMP2A and CHMP3...could
            assemble in vitro into helical tubular structures"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18687924
    review:
      summary: >-
        Protein binding annotation based on CHMP2A-CHMP3 interaction.
      action: MODIFY
      reason: >-
        "Protein binding" is too vague and uninformative. The specific interaction
        is CHMP2A binding to form helical polymers. More specific terms should
        be used.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:18687924
          supporting_text: Aug 7. Helical structures of ESCRT-III are 
            disassembled by VPS4.
  - term:
      id: GO:0016236
      label: macroautophagy
    evidence_type: TAS
    original_reference_id: PMID:20588296
    review:
      summary: >-
        CHMP3 functions in macroautophagy as part of ESCRT-III.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for autophagy. MVBs fuse with autophagosomes.

      supported_by:
        - reference_id: PMID:20588296
          supporting_text: "Jun 30. Membrane budding and scission by the ESCRT machinery:
            it's all in the neck."
  - term:
      id: GO:0061763
      label: multivesicular body-lysosome fusion
    evidence_type: IMP
    original_reference_id: PMID:16554368
    review:
      summary: >-
        Mutant phenotype evidence for CHMP3 role in MVB-lysosome fusion.
      action: ACCEPT
      reason: >-
        hVps24 depletion causes MVBs to accumulate with impaired lysosome fusion.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "impaired fusion with lyso-bisphosphatidic acid-positive
            late endosomes/lysosomes"

  - term:
      id: GO:2000641
      label: regulation of early endosome to late endosome transport
    evidence_type: IMP
    original_reference_id: PMID:16554368
    review:
      summary: >-
        CHMP3 regulates early to late endosome transport.
      action: ACCEPT
      reason: >-
        hVps24 is required for transport of EGFR from early endosomes to
        late endosomes/lysosomes.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "transport of the receptor from early endosomes to lysosomes"

  - term:
      id: GO:0005770
      label: late endosome
    evidence_type: IDA
    original_reference_id: PMID:16554368
    review:
      summary: >-
        Direct evidence for CHMP3 localization to late endosomes.
      action: ACCEPT
      reason: >-
        Primary localization site for endogenous hVps24.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: "Like Tsg101, endogenous hVps24 localized mainly to late
            endosomes."

  - term:
      id: GO:0000815
      label: ESCRT III complex
    evidence_type: TAS
    original_reference_id: PMID:20588296
    review:
      summary: >-
        TAS evidence for CHMP3 as ESCRT-III component.
      action: ACCEPT
      reason: >-
        Well-established core function.

      supported_by:
        - reference_id: PMID:20588296
          supporting_text: "Jun 30. Membrane budding and scission by the ESCRT machinery:
            it's all in the neck."
  - term:
      id: GO:0036258
      label: multivesicular body assembly
    evidence_type: TAS
    original_reference_id: PMID:20588296
    review:
      summary: >-
        CHMP3 functions in MVB assembly.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function.

      supported_by:
        - reference_id: PMID:20588296
          supporting_text: "Jun 30. Membrane budding and scission by the ESCRT machinery:
            it's all in the neck."
  - term:
      id: GO:0039702
      label: viral budding via host ESCRT complex
    evidence_type: TAS
    original_reference_id: PMID:20588296
    review:
      summary: >-
        CHMP3 functions in viral budding.
      action: ACCEPT
      reason: >-
        Well-established ESCRT-III function hijacked by viruses.

      supported_by:
        - reference_id: PMID:20588296
          supporting_text: "Jun 30. Membrane budding and scission by the ESCRT machinery:
            it's all in the neck."
  - term:
      id: GO:0000815
      label: ESCRT III complex
    evidence_type: TAS
    original_reference_id: PMID:21118109
    review:
      summary: >-
        Additional TAS evidence for ESCRT-III membership.
      action: ACCEPT
      reason: >-
        Core function.

      supported_by:
        - reference_id: PMID:21118109
          supporting_text: The role of ESCRT proteins in fusion events involving
            lysosomes, endosomes and autophagosomes.
  - term:
      id: GO:0071985
      label: multivesicular body sorting pathway
    evidence_type: TAS
    original_reference_id: PMID:21118109
    review:
      summary: >-
        TAS evidence for MVB sorting pathway function.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function.

      supported_by:
        - reference_id: PMID:21118109
          supporting_text: The role of ESCRT proteins in fusion events involving
            lysosomes, endosomes and autophagosomes.
  - term:
      id: GO:0097352
      label: autophagosome maturation
    evidence_type: TAS
    original_reference_id: PMID:21118109
    review:
      summary: >-
        TAS evidence for role in autophagosome maturation.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for autophagy.

      supported_by:
        - reference_id: PMID:21118109
          supporting_text: The role of ESCRT proteins in fusion events involving
            lysosomes, endosomes and autophagosomes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18385515
    review:
      summary: >-
        Protein binding based on interactions with LIP5 and VPS4.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. Specific interactions with LIP5/VTA1
        and VPS4 should be captured with more specific terms.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:18385515
          supporting_text: Apr 2. Novel interactions of ESCRT-III with LIP5 and 
            VPS4 and their implications for ESCRT-III disassembly.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23105106
    review:
      summary: >-
        Protein binding based on LIP5 interactions.
      action: MODIFY
      reason: >-
        "Protein binding" is too vague.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:23105106
          supporting_text: 2012 Oct 26. Interactions of the human LIP5 
            regulatory protein with endosomal sorting complexes required for 
            transport.
  - term:
      id: GO:0000815
      label: ESCRT III complex
    evidence_type: IDA
    original_reference_id: PMID:24878737
    review:
      summary: >-
        Direct evidence for ESCRT-III complex membership from structural studies.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:24878737
          supporting_text: "Structure of cellular ESCRT-III spirals"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23051622
    review:
      summary: >-
        Protein binding annotation.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. Should specify the binding partner.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:23051622
          supporting_text: ESCRT-III CHMP2A and CHMP3 form variable helical 
            polymers in vitro and act synergistically during HIV-1 budding.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:16740483
    review:
      summary: >-
        CHMP3 localizes to plasma membrane during viral budding and ESCRT function.
      action: ACCEPT
      reason: >-
        ESCRT-III assembles at plasma membrane for membrane fission events.
      supported_by:
        - reference_id: PMID:16740483
          supporting_text: "Structural basis for budding by the ESCRT-III factor CHMP3"

  - term:
      id: GO:0019076
      label: viral release from host cell
    evidence_type: IMP
    original_reference_id: PMID:23051622
    review:
      summary: >-
        CHMP3 functions in viral release from host cells.
      action: ACCEPT
      reason: >-
        ESCRT-III is required for enveloped virus budding and release.

      supported_by:
        - reference_id: PMID:23051622
          supporting_text: ESCRT-III CHMP2A and CHMP3 form variable helical 
            polymers in vitro and act synergistically during HIV-1 budding.
  - term:
      id: GO:0019076
      label: viral release from host cell
    evidence_type: IGI
    original_reference_id: PMID:23051622
    review:
      summary: >-
        Genetic interaction evidence for role in viral release.
      action: ACCEPT
      reason: >-
        ESCRT-III function in viral budding.

      supported_by:
        - reference_id: PMID:23051622
          supporting_text: ESCRT-III CHMP2A and CHMP3 form variable helical 
            polymers in vitro and act synergistically during HIV-1 budding.
  - term:
      id: GO:0031210
      label: phosphatidylcholine binding
    evidence_type: IMP
    original_reference_id: PMID:18687924
    review:
      summary: >-
        CHMP3 binds phosphatidylcholine in membrane targeting.
      action: ACCEPT
      reason: >-
        CHMP2A-CHMP3 copolymers show cooperative membrane targeting. UniProt
        notes selective binding to phosphoinositides including PtdIns(3,5)P2.
      supported_by:
        - reference_id: PMID:18687924
          supporting_text: "CHMP2A and CHMP3 copolymerized in solution, and their
            membrane targeting was cooperatively enhanced on planar lipid bilayers"

  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IDA
    original_reference_id: PMID:16740483
    review:
      summary: >-
        CHMP3 localizes to cytoplasmic vesicles.
      action: ACCEPT
      reason: >-
        CHMP3 associates with various vesicular compartments.

      supported_by:
        - reference_id: PMID:16740483
          supporting_text: Structural basis for budding by the ESCRT-III factor 
            CHMP3.
  - term:
      id: GO:0039702
      label: viral budding via host ESCRT complex
    evidence_type: IMP
    original_reference_id: PMID:16740483
    review:
      summary: >-
        Mutant phenotype evidence for CHMP3 role in viral budding.
      action: ACCEPT
      reason: >-
        CHMP3 structural studies show basis for budding function.
      supported_by:
        - reference_id: PMID:16740483
          supporting_text: "Structural basis for budding by the ESCRT-III factor CHMP3"

  - term:
      id: GO:0039702
      label: viral budding via host ESCRT complex
    evidence_type: IMP
    original_reference_id: PMID:23051622
    review:
      summary: >-
        Additional mutant phenotype evidence for viral budding role.
      action: ACCEPT
      reason: >-
        Core ESCRT-III function.

      supported_by:
        - reference_id: PMID:23051622
          supporting_text: ESCRT-III CHMP2A and CHMP3 form variable helical 
            polymers in vitro and act synergistically during HIV-1 budding.
  - term:
      id: GO:0044790
      label: suppression of viral release by host
    evidence_type: IMP
    original_reference_id: PMID:16740483
    review:
      summary: >-
        Overexpression of CHMP3 suppresses HIV-1 release.
      action: ACCEPT
      reason: >-
        UniProt notes that CHMP3 overexpression strongly inhibits HIV-1 release.
        This reflects the ability of excess ESCRT-III to block normal viral
        budding.
      supported_by:
        - reference_id: PMID:16740483
          supporting_text: "Structural basis for budding by the ESCRT-III factor CHMP3"

  - term:
      id: GO:0051258
      label: protein polymerization
    evidence_type: IDA
    original_reference_id: PMID:23051622
    review:
      summary: >-
        CHMP3 participates in ESCRT-III polymerization.
      action: ACCEPT
      reason: >-
        CHMP2A-CHMP3 form helical polymers (PMID:18687924).
      supported_by:
        - reference_id: PMID:18687924
          supporting_text: "We found that the ESCRT-III proteins CHMP2A and CHMP3...could
            assemble in vitro into helical tubular structures"

        - reference_id: PMID:23051622
          supporting_text: ESCRT-III CHMP2A and CHMP3 form variable helical 
            polymers in vitro and act synergistically during HIV-1 budding.
  - term:
      id: GO:1990381
      label: ubiquitin-specific protease binding
    evidence_type: IPI
    original_reference_id: PMID:18395747
    review:
      summary: >-
        CHMP3 binds STAMBP/AMSH, a ubiquitin-specific protease.
      action: ACCEPT
      reason: >-
        CHMP3 interacts with STAMBP to recruit deubiquitinase activity to
        ESCRT-III. Well-characterized interaction.
      supported_by:
        - reference_id: PMID:18395747
          supporting_text: "Structural basis for autoinhibition of ESCRT-III CHMP3"

  - term:
      id: GO:0010824
      label: regulation of centrosome duplication
    evidence_type: IMP
    original_reference_id: PMID:20616062
    review:
      summary: >-
        CHMP3 depletion affects centrosome numbers.
      action: KEEP_AS_NON_CORE
      reason: >-
        ESCRT-III depletion causes centrosome amplification. Secondary function.
      supported_by:
        - reference_id: PMID:20616062
          supporting_text: "depletion of individual ESCRT-III and VPS4 proteins also
            altered centrosome and spindle pole numbers"

  - term:
      id: GO:1903541
      label: regulation of exosomal secretion
    evidence_type: IMP
    original_reference_id: PMID:22660413
    negated: true
    review:
      summary: >-
        NOT annotation per GOA indicating CHMP3 is not directly involved in regulation
        of exosomal secretion.
      action: ACCEPT
      reason: >-
        GOA includes a NOT qualifier for this term with PMID:22660413; we accept the
        negative annotation.
      supported_by:
        - reference_id: PMID:22660413
          supporting_text: "Syndecan-syntenin-ALIX regulates the biogenesis of exosomes"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14519844
    review:
      summary: >-
        Protein binding based on VPS4A interaction.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. Specific interaction with VPS4A
        should be captured.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:14519844
          supporting_text: Divergent retroviral late-budding domains recruit 
            vacuolar protein sorting factors by using alternative adaptor 
            proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14505570
    review:
      summary: >-
        Protein binding based on CHMP4A interaction.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:14505570
          supporting_text: The protein network of HIV budding.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: >-
        CHMP3 detected in extracellular exosomes by proteomics.
      action: ACCEPT
      reason: >-
        ESCRT-III components can be found in exosomes, possibly reflecting
        their role in ILV/exosome biogenesis.
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: "Large-scale proteomics and phosphoproteomics of urinary
            exosomes"

# Reactome annotations - cytosol localization
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3159232
    review:
      summary: >-
        Reactome annotation for cytosolic localization (HIV virion budding).
      action: ACCEPT
      reason: >-
        CHMP3 exists in autoinhibited form in cytosol.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917693
    review:
      summary: >-
        Reactome annotation for cytosolic localization (ESCRT disassembly).
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917700
    review:
      summary: >-
        Reactome annotation for cytosolic localization (MVB vesicle formation).
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668389
    review:
      summary: >-
        Reactome annotation for cytosolic localization (NE reformation).
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668395
    review:
      summary: >-
        Reactome annotation for cytosolic localization.
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668398
    review:
      summary: >-
        Reactome annotation for cytosolic localization.
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668405
    review:
      summary: >-
        Reactome annotation for cytosolic localization.
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668415
    review:
      summary: >-
        Reactome annotation for cytosolic localization.
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9668419
    review:
      summary: >-
        Reactome annotation for cytosolic localization.
      action: ACCEPT
      reason: >-
        Cytosolic pool of CHMP3.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21543490
    review:
      summary: >-
        Protein binding based on VTA1/VPS4A interaction.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:21543490
          supporting_text: Mechanism of inhibition of retrovirus release from 
            cells by interferon-induced gene ISG15.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19525971
    review:
      summary: >-
        Protein binding from autoinhibition structural study.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. This study characterized CHMP2A
        interaction and autoinhibition.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:19525971
          supporting_text: Jun 14. Structural basis for ESCRT-III protein 
            autoinhibition.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings:
      - statement: CHMP3 contains Snf7 domain associated with vacuolar transport
          functions

  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: Vps24/CHMP3 function in MVB biogenesis is conserved from 
          yeast to human

  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []

  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []

  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []

  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []

  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []

  - id: PMID:14505570
    title: The protein network of HIV budding.
    findings:
      - statement: CHMP3/hVps24 is part of the human class E protein network for
          MVB biogenesis
      - statement: Dominant-negative CHMP mutants arrest HIV-1 budding

  - id: PMID:14519844
    title: Divergent retroviral late-budding domains recruit vacuolar protein 
      sorting factors by using alternative adaptor proteins.
    findings:
      - statement: CHMP3 interacts with CHMP2A and VPS4A

  - id: PMID:16505166
    title: Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a 
      conserved VSL region in Vta1.
    findings:
      - statement: ESCRT-III recycling by VPS4

  - id: PMID:16554368
    title: The ESCRT-III subunit hVps24 is required for degradation but not 
      silencing of the epidermal growth factor receptor.
    findings:
      - statement: hVps24 localizes mainly to late endosomes
      - statement: Required for EGFR degradation and transport to lysosomes
      - statement: Depletion causes accumulation in small MVEs with impaired 
          lysosome fusion
      - statement: Not required for termination of EGF signaling

  - id: PMID:16740483
    title: Structural basis for budding by the ESCRT-III factor CHMP3.
    findings:
      - statement: Crystal structure of CHMP3 at 2.8 angstrom resolution
      - statement: CHMP3 overexpression inhibits HIV-1 release

  - id: PMID:17984323
    title: Functional multivesicular bodies are required for autophagic 
      clearance of protein aggregates associated with neurodegenerative disease.
    findings:
      - statement: ESCRT-III function is required for autophagic clearance

  - id: PMID:18385515
    title: Novel interactions of ESCRT-III with LIP5 and VPS4 and their 
      implications for ESCRT-III disassembly.
    findings:
      - statement: CHMP3 interacts with LIP5 and VPS4

  - id: PMID:18395747
    title: Structural basis for autoinhibition of ESCRT-III CHMP3.
    findings:
      - statement: CHMP3 exists in autoinhibited conformation
      - statement: Interaction with STAMBP relieves autoinhibition

  - id: PMID:18687924
    title: Helical structures of ESCRT-III are disassembled by VPS4.
    findings:
      - statement: CHMP2A and CHMP3 assemble into helical tubular structures in 
          vitro
      - statement: VPS4 disassembles the tubes upon ATP hydrolysis
      - statement: CHMP2A-CHMP3 copolymers expose membrane interaction sites 
          externally

  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings:
      - statement: CHMP3 detected in urinary exosomes

  - id: PMID:19234443
    title: Membrane scission by the ESCRT-III complex.
    findings:
      - statement: ESCRT-III mediates membrane scission

  - id: PMID:19525971
    title: Structural basis for ESCRT-III protein autoinhibition.
    findings:
      - statement: Crystal structure of autoinhibited CHMP3
      - statement: Characterization of CHMP2A interaction and autoinhibition 
          mechanism

  - id: PMID:20588296
    title: 'Membrane budding and scission by the ESCRT machinery: it''s all in the neck.'
    findings:
      - statement: Review of ESCRT-III function in membrane remodeling

  - id: PMID:20616062
    title: Human ESCRT-III and VPS4 proteins are required for centrosome and 
      spindle maintenance.
    findings:
      - statement: Depletion of any ESCRT-III protein inhibits abscission
      - statement: ESCRT-III depletion causes centrosome amplification and 
          multipolar spindles
      - statement: CHMP3 and CHMP4 localize to kinetochores

  - id: PMID:21118109
    title: The role of ESCRT proteins in fusion events involving lysosomes, 
      endosomes and autophagosomes.
    findings: []

  - id: PMID:21543490
    title: Mechanism of inhibition of retrovirus release from cells by 
      interferon-induced gene ISG15.
    findings:
      - statement: CHMP3 interacts with VTA1 and VPS4A

  - id: PMID:21827950
    title: Structural basis for ESCRT-III CHMP3 recruitment of AMSH.
    findings:
      - statement: Crystal structure of CHMP3 C-terminus with STAMBP/AMSH
      - statement: CHMP3 recruits AMSH deubiquitinase to ESCRT-III

  - id: PMID:22660413
    title: Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.
    findings:
      - statement: ESCRT-III involved in exosome biogenesis

  - id: PMID:23051622
    title: ESCRT-III CHMP2A and CHMP3 form variable helical polymers in vitro 
      and act synergistically during HIV-1 budding.
    findings: []

  - id: PMID:23105106
    title: Interactions of the human LIP5 regulatory protein with endosomal 
      sorting complexes required for transport.
    findings:
      - statement: CHMP3 interacts with LIP5

  - id: PMID:24482116
    title: ESCRT machinery is required for plasma membrane repair.
    findings:
      - statement: ESCRT-III mediates plasma membrane resealing after injury

  - id: PMID:24878737
    title: Structure of cellular ESCRT-III spirals and their relationship to HIV
      budding.
    findings:
      - statement: Cryo-EM structures of ESCRT-III spirals at plasma membrane
      - statement: CHMP3 is part of ESCRT-III assemblies for HIV budding

  - id: PMID:26040712
    title: Spastin and ESCRT-III coordinate mitotic spindle disassembly and 
      nuclear envelope sealing.
    findings:
      - statement: ESCRT-III localizes to kinetochores and midbody

  - id: PMID:26040713
    title: ESCRT-III controls nuclear envelope reformation.
    findings:
      - statement: ESCRT-III localizes to nuclear envelope fenestrations during 
          telophase
      - statement: CHMP3 depletion impairs NE integrity
      - statement: ESCRT-III required for sealing holes in forming NE

  - id: PMID:36604498
    title: Structural basis of CHMP2A-CHMP3 ESCRT-III polymer assembly and 
      membrane cleavage.
    findings: []

  - id: Reactome:R-HSA-3159232
    title: Recruitment Of HIV Virion Budding Machinery
    findings: []

  - id: Reactome:R-HSA-917693
    title: ESCRT Disassembly
    findings: []

  - id: Reactome:R-HSA-917700
    title: MVB Vesicle Formation
    findings: []

  - id: Reactome:R-HSA-9668389
    title: VPS4 binds ESCRT-III assemblies at nuclear envelope (NE) 
      fenestrations
    findings: []

  - id: Reactome:R-HSA-9668395
    title: CHMP7 binds CC2D1B
    findings: []

  - id: Reactome:R-HSA-9668398
    title: CHMP7 binds CHMP4B, which recruits other subunits of the ESCRT-III 
      complex
    findings: []

  - id: Reactome:R-HSA-9668405
    title: SPAST (spastin) binds the IST1 subunit of ESCRT-III at the sites of 
      microtubule attachment to chromatin
    findings: []

  - id: Reactome:R-HSA-9668415
    title: VPS4 mediates disassembly of ESCRTIII subunits to promote sealing of 
      holes in the nuclear envelope
    findings: []

  - id: Reactome:R-HSA-9668419
    title: SPAST (spastin) mediates the severing of microtubules at chromosome 
      attachment sites
    findings: []
  - id: file:human/CHMP3/CHMP3-deep-research-falcon.md
    title: Deep research report on CHMP3
    findings: []

proposed_new_terms: []

suggested_questions:
  - question: What is the precise sequence of CHMP subunit assembly and 
      VPS4-driven remodeling during membrane scission?
  - question: How do different ESCRT-III paralogs contribute to 
      compartment-specific functions (MVB vs. lysosomal microautophagy)?
  - question: What regulates CHMP3 recruitment to different cellular sites 
      (endosomes vs. midbody vs. nuclear envelope)?

suggested_experiments:
  - description: Live-cell imaging of CHMP3 dynamics during nuclear envelope 
      reformation at higher temporal resolution
  - description: Systematic comparison of CHMP3 knockout vs knockdown phenotypes
      to assess functional redundancy
  - description: Reconstitution of CHMP3-containing ESCRT-III assemblies with 
      defined subunit stoichiometry