VMP1

id: Q96GC9
gene_symbol: VMP1
product_type: PROTEIN
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'VMP1 (Vacuole membrane protein 1; also TMEM49) is a multi-pass integral
  membrane protein of the endoplasmic reticulum belonging to the VMP1/VTT-domain (DedA-related)
  family. Its core molecular activity is phospholipid scramblase: in vitro, purified
  VMP1 reconstituted into liposomes equilibrates phospholipids between bilayer leaflets
  in an ATP- and calcium-independent manner with little headgroup specificity, scrambling
  phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and cholesterol.
  Through this activity VMP1 reequilibrates the leaflets of the ER membrane as lipids
  are extracted by the bridge-like lipid transfer protein ATG2 during autophagosome
  biogenesis, acting together with the related ER scramblase TMEM41B and the autophagosomal
  scramblase ATG9. VMP1 is essential for early autophagosome formation and for the
  disengagement of isolation membranes from the ER; mechanistically it promotes SERCA
  (ATP2A) calcium-pump activity by competing with the inhibitors phospholamban (PLN)
  and sarcolipin (SLN), thereby controlling ER contacts with isolation membranes,
  lipid droplets, mitochondria and endosomes. Beyond autophagy, VMP1 scramblase activity
  is required for the release of lipoproteins from the ER membrane into the ER lumen,
  for normal cellular distribution of cholesterol and phosphatidylserine, and is exploited
  by flaviviruses and coronaviruses to remodel ER membranes into viral replication
  organelles. VMP1 is induced in acute pancreatitis and contributes to cytoplasmic
  vacuolization, and an early study reported a plasma-membrane pool involved in cell-cell
  adhesion and tight junction formation.'
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to
      orthologs by curator judgment of sequence similarity.
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - 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, accompanied by conservative changes to GO terms applied by
      UniProt.
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000054
    title: Gene Ontology annotation based on curation of intracellular localizations
      of expressed fusion proteins in living cells.
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to
      orthologs using Ensembl Compara.
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on inter-ontology
      links.
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:17724469
    title: Reduced expression of vacuole membrane protein 1 affects the invasion capacity
      of tumor cells.
    findings:
      - statement: VMP1 was reported as a plasma membrane protein that participates in
          initial cell-cell contacts and tight junction formation, interacting with ZO-1/TJP1.
        supporting_text: We show for the first time that Vmp1 is a plasma membrane protein
          and an essential component of initial cell-cell contacts and tight junction
          formation. It interacts with the tight junction protein Zonula Occludens-1 and
          colocalizes in spots between neighboring HEK293 cells.
      - statement: Downregulation of VMP1 reduces cell adhesion and increases invasiveness.
        supporting_text: Downregulation of VMP1 by RNAi results in loss of cell adherence,
          and increases the invasion capacity of the non-invasive kidney cancer cell line
          Caki-2.
  - id: PMID:19056683
    title: The TP53INP2 protein is required for autophagy in mammalian cells.
    findings:
      - statement: TP53INP2 interacts with the autophagosome transmembrane protein VMP1,
          which is proposed to help recruit LC3/GABARAP proteins to the autophagosome
          membrane.
        supporting_text: TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related
          proteins to the autophagosome membrane by interacting with the transmembrane
          protein VMP1.
  - id: PMID:23316280
    title: The VMP1-Beclin 1 interaction regulates autophagy induction.
    findings:
      - statement: The VMP1 C-terminal hydrophilic domain binds the BH3 motif of Beclin
          1, recruiting and activating the class III PI3K (hVps34) complex at the autophagosome
          formation site.
        supporting_text: This is achieved through its direct binding to the BH3 motif
          of Beclin 1 leading to the formation of a complex with the Class III phosphatidylinositol-3
          kinase (PI3K) hVps34, a key positive regulator of autophagy, at the site where
          autophagosomes are generated.
  - id: PMID:28890335
    title: The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity
      to Control ER-Isolation Membrane Contacts for Autophagosome Formation.
    findings:
      - statement: VMP1 is an ER-localized autophagy protein that controls ER-isolation
          membrane contacts; its loss stably traps isolation membranes on the ER and
          blocks autophagosome formation.
        supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
          controls ER-IM contacts. Loss of VMP1 causes stable association of IMs with the
          ER, thus blocking autophagosome formation.
      - statement: VMP1 promotes SERCA activity by interacting with SERCA and preventing
          formation of the SERCA/PLN/SLN inhibitory complex, and modulates ER contacts
          with lipid droplets, mitochondria and endosomes.
        supporting_text: VMP1 controls contact formation by promoting SERCA (sarco[endo]plasmic
          reticulum calcium ATPase) activity. VMP1 interacts with SERCA and prevents formation
          of the SERCA/PLN/SLN inhibitory complex. VMP1 also modulates ER contacts with
          lipid droplets, mitochondria, and endosomes.
  - id: PMID:30093494
    title: Genome-wide CRISPR screen identifies TMEM41B as a gene required for autophagosome
      formation.
    findings:
      - statement: A genome-wide CRISPR screen identified TMEM41B, a VTT-domain protein
          related to VMP1, as required for autophagosome formation; VMP1 interacts with
          TMEM41B and shares the VTT domain.
        supporting_text: Genome-wide CRISPR screen identifies TMEM41B as a gene required
          for autophagosome formation.
  - id: PMID:30933966
    title: CRISPR screening using an expanded toolkit of autophagy reporters identifies
      TMEM41B as a novel autophagy factor.
    findings:
      - statement: A CRISPR screen using autophagy reporters identified TMEM41B (a VMP1
          paralog) as required for phagophore maturation, supporting a shared role of
          VTT-domain ER proteins in autophagosome formation.
        supporting_text: TMEM41B, is required for phagophore maturation. TMEM41B is an
          integral endoplasmic reticulum
  - id: PMID:31526472
    title: A critical role of VMP1 in lipoprotein secretion.
    findings:
      - statement: VMP1, but not other autophagy genes, is required for release of lipoproteins
          from the ER membrane into the ER lumen; its loss causes neutral lipid accumulation
          in the ER bilayer and impaired lipoprotein secretion.
        supporting_text: the release of lipoproteins from the ER membrane requires VMP1,
          an ER transmembrane protein essential for autophagy and certain types of secretion.
          Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein
          accumulation in the intestine and liver.
      - statement: In VMP1-depleted cells neutral lipids accumulate within the ER membrane
          bilayer, affecting lipoprotein secretion.
        supporting_text: In VMP1-depleted cells, neutral lipids accumulate within lipid
          bilayers of the ER membrane, thus affecting lipoprotein secretion.
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings:
      - statement: VMP1 was reported as an interactor in a systematic binary (Y2H) human
          interactome map.
        supporting_text: A reference map of the human binary protein interactome.
  - id: PMID:33850023
    title: A model for a partnership of lipid transfer proteins and scramblases in membrane
      expansion and organelle biogenesis.
    findings:
      - statement: In vitro assays show VMP1 (with TMEM41B and ATG9) is a phospholipid
          scramblase that reequilibrates membrane leaflets; VMP1 and TMEM41B interact
          with the lipid transfer protein ATG2A.
        supporting_text: In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases.
          We propose a model wherein membrane expansion results from the partnership of
          a lipid transfer protein, moving lipids between the cytosolic leaflets of apposed
          organelles, and scramblases that reequilibrate the leaflets of donor and acceptor
          organelle membranes as lipids are depleted or augmented.
      - statement: Purified VMP1 reconstituted into liposomes scrambles NBD-PE and NBD-PC,
          with no specificity to a particular glycerolipid; ATG2A is retained by both
          TMEM41B and VMP1.
        supporting_text: lipid scrambling by TMEM41B/VMP1, TMEM41B, and VMP1 are not specific
          to a particular glycerolipid (SI Appendix, Fig. 1D) as both NBD-PE and NBD-phosphatidylcholine
          (PC) are substrates.
  - id: PMID:33929485
    title: TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol
      and phosphatidylserine.
    findings:
      - statement: TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs
          the normal cellular distribution of cholesterol and phosphatidylserine.
        supporting_text: TMEM41B and VMP1 are phospholipid scramblases whose deficiency
          impairs the normal cellular distribution of cholesterol and phosphatidylserine.
      - statement: Purified VMP1 in liposomes scrambles NBD-PE, PC and PS; activity is
          ATP-independent and not affected by calcium and shows no headgroup specificity.
        supporting_text: The scramblase activity of TMEM41B/VMP1 did not depend on ATP
          and was not affected by calcium (Fig. S3, D and E). Of note, the scramblase activity
          of TMEM41B was not impacted by the presence of VMP1 (Fig. 4 B) and vice versa,
          indicating that TMEM41B's or VMP1's scramblase activity does not require the
          other in vitro. Moreover, no apparent specificity toward the head groups of
          phospholipids was detected
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings:
      - statement: VMP1 was reported as an interactor (e.g. with ERGIC3) in a large-scale
          affinity-purification interactome study.
        supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
          of the human interactome.
  - id: file:human/VMP1/VMP1-deep-research-falcon.md
    title: Deep research report on VMP1 (Q96GC9)
    findings:
      - statement: VMP1 is an ER-resident DedA/VTT-domain phospholipid scramblase that
          cooperates with TMEM41B, ATG9 and ATG2 in autophagosome biogenesis and broader
          ER-derived membrane dynamics.
        supporting_text: VMP1 is a core ER scramblase that underpins autophagosome membrane
          biogenesis by cooperating with ATG2 and ATG9 and is broadly required for ER-derived
          membrane remodeling, including lipid droplets, lipoproteins, and viral DMVs
existing_annotations:
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: VMP1 is an ER-resident multi-pass membrane protein; ER localization is
        the well-established core site of action.
      action: ACCEPT
      reason: ER localization is strongly supported by phylogenetic inference and by
        multiple experimental studies showing VMP1 resides on the ER membrane where it
        acts as a scramblase during autophagosome biogenesis and lipoprotein secretion.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
  - term:
      id: GO:0012505
      label: endomembrane system
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: VMP1 is a component of the endomembrane system, consistent with its ER/ERGIC/vacuole
        membrane localization.
      action: ACCEPT
      reason: This broad cellular component is correct but uninformative; it is retained
        as a non-misleading parent of the more specific ER membrane localization. The
        more specific endoplasmic reticulum term better captures the core site.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are integral membrane proteins of the endoplasmic
            reticulum
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: VMP1 is required for early autophagosome formation, reequilibrating ER
        membrane leaflets as lipids are extracted by ATG2; this is a core biological
        process.
      action: ACCEPT
      reason: Autophagosome assembly is supported by phylogenetic inference and by extensive
        experimental evidence (CRISPR/IM-contact and scramblase studies). This is one
        of the core processes of VMP1.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: Loss of VMP1 causes stable association of IMs with the ER,
            thus blocking autophagosome formation.
        - reference_id: PMID:33850023
          supporting_text: TMEM41B and VMP1 reside in a complex on the ER and are necessary
            during autophagosome expansion
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: VMP1 is an integral multi-pass membrane protein; the bare membrane term
        is correct but very general.
      action: ACCEPT
      reason: Generic membrane localization is accurate (multi-pass membrane protein)
        but uninformative; the more specific endoplasmic reticulum membrane term is preferred.
        Retained as a non-misleading parent.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are integral membrane proteins of the endoplasmic
            reticulum
  - term:
      id: GO:0007030
      label: Golgi organization
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Golgi organization is an IBA-inferred process for the VMP1 family but
        is not supported by experimental evidence for human VMP1, whose characterized
        roles are at the ER (autophagy, lipoprotein secretion, lipid distribution).
      action: KEEP_AS_NON_CORE
      reason: This phylogenetically-inferred term likely reflects roles of non-mammalian
        family members. No direct evidence supports a Golgi-organization role for human
        VMP1; it is not a core function. Retained as non-core rather than removed because
        IBA across the family carries some weight and VMP1 does localize to the ERGIC.
      supported_by:
        - reference_id: file:human/VMP1/VMP1-deep-research-falcon.md
          supporting_text: VMP1 is a core ER scramblase that underpins autophagosome membrane
            biogenesis by cooperating with ATG2 and ATG9
  - term:
      id: GO:0005774
      label: vacuolar membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Vacuole membrane localization is inferred from the UniProt subcellular-location
        keyword (by similarity to the mouse ortholog) and reflects the historical naming
        of the protein.
      action: KEEP_AS_NON_CORE
      reason: This IEA term derives from a by-similarity UniProt subcellular location;
        the lysosome/vacuole pool is plausible but is not the characterized site of human
        VMP1 action, which is the ER membrane. Retained as non-core.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are integral membrane proteins of the endoplasmic
            reticulum
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ER membrane is the core site of VMP1 action and is well supported experimentally.
      action: ACCEPT
      reason: This is the most informative and accurate cellular component for VMP1.
        It is independently supported by IDA evidence (PMID:28890335) and by the scramblase
        studies.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: A plasma-membrane pool was reported in one early study linking VMP1 to
        cell-cell adhesion, and the UniProt location keyword records cell membrane.
      action: KEEP_AS_NON_CORE
      reason: Plasma membrane localization rests on a single early study (PMID:17724469);
        the dominant and mechanistically characterized localization is the ER. Retained
        as non-core rather than core, since the adhesion role is not the principal function.
      supported_by:
        - reference_id: PMID:17724469
          supporting_text: we show for the first time that Vmp1 is a plasma membrane protein
            and an essential component of initial cell-cell contacts and tight junction
            formation.
  - term:
      id: GO:0006869
      label: lipid transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: VMP1 mediates transbilayer movement (scrambling) of phospholipids and
        cholesterol and is required for lipoprotein release; the broad lipid transport
        term is consistent with these roles.
      action: ACCEPT
      reason: Derived from the UniProt Lipid transport keyword, this broad term is correct
        given VMP1's scramblase activity and roles in lipid distribution and lipoprotein
        secretion. The more specific molecular function is phospholipid scramblase activity.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are phospholipid scramblases whose deficiency
            impairs the normal cellular distribution of cholesterol and phosphatidylserine.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: VMP1 is a core autophagy protein required for autophagosome formation.
      action: ACCEPT
      reason: Autophagy is well supported by experimental evidence (also annotated IDA
        from PMID:28890335). The more specific child autophagosome assembly is the better
        descriptor, but this broad term is not wrong.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: Loss of VMP1 causes stable association of IMs with the ER,
            thus blocking autophagosome formation.
  - term:
      id: GO:0007155
      label: cell adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: A cell-adhesion role derives from the UniProt Cell adhesion keyword, based
        on the single study reporting VMP1 at the plasma membrane in cell-cell contacts.
      action: KEEP_AS_NON_CORE
      reason: Cell adhesion is supported only by one early study (PMID:17724469) and
        is peripheral to the predominant ER scramblase function. Retained as a non-core
        process rather than removed because the underlying experimental evidence (cell-cell
        adhesion, tight junctions) does exist.
      supported_by:
        - reference_id: PMID:17724469
          supporting_text: our findings establish Vmp1 to be a novel cell-cell adhesion
            protein
  - term:
      id: GO:0017121
      label: plasma membrane phospholipid scrambling
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: This process term was inferred automatically (inter-ontology link) from
        the phospholipid scramblase activity molecular function. VMP1 scrambles lipids
        at the ER membrane, not at the plasma membrane.
      action: MARK_AS_OVER_ANNOTATED
      reason: The inter-ontology inference incorrectly localizes VMP1 scrambling to the
        plasma membrane. The experimentally documented scramblase activity occurs at
        the ER membrane (and in vitro liposomes), so the plasma-membrane-specific process
        term over-specifies an incorrect location.
      supported_by:
        - reference_id: PMID:33850023
          supporting_text: TMEM41B and VMP1 reside in a complex on the ER and are necessary
            during autophagosome expansion
  - term:
      id: GO:0033116
      label: endoplasmic reticulum-Golgi intermediate compartment membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ERGIC membrane localization derives from the UniProt subcellular-location
        keyword (by similarity) and is consistent with VMP1 acting in the early secretory/ER
        compartment.
      action: KEEP_AS_NON_CORE
      reason: This by-similarity location is plausible and consistent with VMP1 biology
        but is less central than the ER membrane. Retained as non-core.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are integral membrane proteins of the endoplasmic
            reticulum
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23316280
    review:
      summary: This IPI captures the VMP1-Beclin 1 (BECN1) interaction that recruits/activates
        the class III PI3K complex during autophagy induction.
      action: ACCEPT
      reason: The generic protein binding term is uninformative on its own, but the underlying
        BECN1 interaction is experimentally validated and functionally meaningful (autophagy
        induction). Per curation policy bare protein binding is not promoted to core;
        kept as supporting evidence with the specific partner recorded.
      supported_by:
        - reference_id: PMID:23316280
          supporting_text: its direct binding to the BH3 motif of Beclin 1 leading to
            the formation of a complex with the Class III phosphatidylinositol-3 kinase
            (PI3K) hVps34
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Protein binding from a high-throughput binary (Y2H) interactome map (interactors
        including CYB5R3, FAM209A, MEOX2, SLC39A9, ERGIC3).
      action: KEEP_AS_NON_CORE
      reason: Bare protein binding from a systematic interactome screen is uninformative
        and the interactors are not part of a characterized VMP1 functional module. Kept
        as non-core supporting evidence rather than removed, as the data are valid interactions.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: A reference map of the human binary protein interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Protein binding from a large-scale affinity-purification interactome (e.g.
        VMP1-ERGIC3).
      action: KEEP_AS_NON_CORE
      reason: Generic protein binding from a high-throughput proteomic network is uninformative
        as a molecular function. Retained as non-core supporting evidence.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
            of the human interactome.
  - term:
      id: GO:0000407
      label: phagophore assembly site
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: VMP1 localizes to ER subdomains in contact with the isolation membrane/phagophore
        during autophagosome formation; the phagophore assembly site location is consistent
        with this and is transferred from the mouse ortholog.
      action: ACCEPT
      reason: VMP1 acts at ER-isolation membrane contact sites where the phagophore forms;
        this localization is supported by the ER-IM contact and autophagosome-formation
        studies and is consistent with the orthology-based transfer.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: isolation membranes (IMs; autophagosome precursors) dynamically
            contact the ER. Here, we demonstrated that the ER-localized metazoan-specific
            autophagy protein EPG-3/VMP1 controls ER-IM contacts.
  - term:
      id: GO:0007566
      label: embryo implantation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Embryo implantation is transferred by orthology from the mouse ortholog
        and likely reflects a pleiotropic developmental consequence of loss of an essential
        autophagy/secretion gene rather than a direct molecular role.
      action: KEEP_AS_NON_CORE
      reason: This acts_upstream_of_or_within annotation transferred from mouse is a downstream
        developmental phenotype, not a core molecular/cellular function of VMP1. No human-specific
        evidence is available. Retained as non-core.
      supported_by:
        - reference_id: file:human/VMP1/VMP1-deep-research-falcon.md
          supporting_text: VMP1 is broadly required for ER-derived membrane remodeling,
            including lipid droplets, lipoproteins, and viral DMVs
  - term:
      id: GO:0042953
      label: lipoprotein transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: VMP1 is required for release of lipoproteins from the ER membrane into
        the ER lumen for secretion; this orthology-transferred term reflects that role.
      action: ACCEPT
      reason: Lipoprotein transport/secretion is a genuine VMP1 function, also directly
        supported by IMP evidence (PMID:31526472). The orthology-based transfer is consistent
        with human evidence.
      supported_by:
        - reference_id: PMID:31526472
          supporting_text: the release of lipoproteins from the ER membrane requires VMP1
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Immunofluorescence (HPA) curation places VMP1 at the endoplasmic reticulum.
      action: ACCEPT
      reason: Direct immunofluorescence localization to the ER agrees with the established
        core site of VMP1 action.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
  - term:
      id: GO:0017128
      label: phospholipid scramblase activity
    evidence_type: IDA
    original_reference_id: PMID:33850023
    review:
      summary: Purified VMP1 reconstituted into liposomes scrambles phospholipids (NBD-PE,
        NBD-PC) between bilayer leaflets; this is the core molecular function of VMP1.
      action: ACCEPT
      reason: Direct in vitro reconstitution demonstrates VMP1 is a phospholipid scramblase.
        This is the central, mechanistically defining molecular function of the protein.
      supported_by:
        - reference_id: PMID:33850023
          supporting_text: In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases.
        - reference_id: PMID:33850023
          supporting_text: both NBD-PE and NBD-phosphatidylcholine (PC) are substrates
  - term:
      id: GO:0017128
      label: phospholipid scramblase activity
    evidence_type: IDA
    original_reference_id: PMID:33929485
    review:
      summary: Independent reconstitution shows purified VMP1 scrambles NBD-PE, PC and
        PS in an ATP- and calcium-independent, headgroup-nonspecific manner.
      action: ACCEPT
      reason: A second independent study directly demonstrates VMP1 phospholipid scramblase
        activity in vitro, corroborating the core molecular function. Duplicate GO ID
        with distinct experimental support is appropriate.
      supported_by:
        - reference_id: PMID:33929485
          supporting_text: TMEM41B and VMP1 are phospholipid scramblases whose deficiency
            impairs the normal cellular distribution of cholesterol and phosphatidylserine.
        - reference_id: PMID:33929485
          supporting_text: The scramblase activity of TMEM41B/VMP1 did not depend on ATP
            and was not affected by calcium
  - term:
      id: GO:0042953
      label: lipoprotein transport
    evidence_type: IMP
    original_reference_id: PMID:31526472
    review:
      summary: Loss-of-function of VMP1 (zebrafish, mouse, cells) blocks release of lipoproteins
        from the ER membrane into the ER lumen, causing lipid accumulation.
      action: ACCEPT
      reason: Strong genetic/IMP evidence across organisms establishes VMP1 as required
        for lipoprotein secretion, downstream of its scramblase activity. A genuine core-related
        process.
      supported_by:
        - reference_id: PMID:31526472
          supporting_text: Loss of vmp1, but not other autophagy-related genes, in zebrafish
            causes lipoprotein accumulation in the intestine and liver.
  - term:
      id: GO:0016240
      label: autophagosome membrane docking
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 controls the dynamic contact (docking/undocking) between isolation
        membranes and the ER; its loss locks isolation membranes onto the ER.
      action: ACCEPT
      reason: The IM-ER contact regulation directly supports a role in autophagosome
        membrane docking dynamics. Mechanistically VMP1 promotes detachment of IMs from
        the ER to allow autophagosome maturation.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: Loss of VMP1 causes stable association of IMs with the ER,
            thus blocking autophagosome formation.
  - term:
      id: GO:0140056
      label: organelle localization by membrane tethering
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 modulates ER membrane contact sites with lipid droplets, mitochondria
        and endosomes (and isolation membranes) by controlling SERCA-dependent calcium
        signaling at these contacts.
      action: ACCEPT
      reason: Experimental evidence shows VMP1 regulates the formation/disassembly of
        ER contacts with multiple organelles, consistent with a role in organelle localization
        by membrane tethering.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: VMP1 also modulates ER contacts with lipid droplets, mitochondria,
            and endosomes.
  - term:
      id: GO:1990456
      label: mitochondrion-endoplasmic reticulum membrane tethering
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 modulates ER-mitochondria contacts as part of its SERCA/calcium-dependent
        control of ER membrane contact sites.
      action: ACCEPT
      reason: The study directly shows VMP1 modulates ER-mitochondria contacts; this
        specific tethering term is supported.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: VMP1 also modulates ER contacts with lipid droplets, mitochondria,
            and endosomes.
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 is required for autophagosome formation; its loss blocks autophagosome
        formation by trapping isolation membranes on the ER.
      action: ACCEPT
      reason: Direct experimental evidence (IDA) for the core autophagosome assembly
        process. Duplicate of the IBA term with experimental support.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: Loss of VMP1 causes stable association of IMs with the ER,
            thus blocking autophagosome formation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28890335
    review:
      summary: This IPI captures the experimentally validated VMP1 interactions with
        SERCA (ATP2A1/2/3), PLN and SLN that underlie VMP1 control of SERCA activity.
      action: KEEP_AS_NON_CORE
      reason: Bare protein binding is uninformative as a molecular function, but the
        underlying SERCA/PLN/SLN interactions are functionally important and are better
        represented by the positive regulation of SERCA activity process term. Kept as
        non-core supporting evidence per curation policy on protein binding.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN
            inhibitory complex.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: Direct evidence places VMP1 on the ER membrane, its core site of action.
      action: ACCEPT
      reason: IDA-supported ER membrane localization; the most informative and accurate
        cellular component for VMP1.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 is directly required for autophagy/autophagosome formation.
      action: ACCEPT
      reason: Direct experimental support for autophagy; consistent with the core role,
        with the more specific autophagosome assembly term also annotated.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: Loss of VMP1 causes stable association of IMs with the ER,
            thus blocking autophagosome formation.
  - term:
      id: GO:1901896
      label: positive regulation of ATPase-coupled calcium transmembrane transporter
        activity
    evidence_type: IDA
    original_reference_id: PMID:28890335
    review:
      summary: VMP1 promotes SERCA (ATP2A) calcium-pump activity by competing with PLN
        and SLN, preventing the inhibitory SERCA/PLN/SLN complex.
      action: ACCEPT
      reason: Directly supported molecular-level regulatory function; VMP1 activation
        of SERCA is the mechanism by which it controls ER membrane contact sites.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN
            inhibitory complex.
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IMP
    original_reference_id: PMID:30933966
    review:
      summary: CRISPR screening of autophagy reporters identifies the VTT-domain ER proteins
        (TMEM41B, with VMP1 as paralog) as required for phagophore maturation/autophagosome
        formation.
      action: ACCEPT
      reason: Genetic screen evidence supports the core autophagosome assembly role of
        VTT-domain ER scramblases. This screen primarily implicates TMEM41B, but VMP1
        is the functionally paralogous ER scramblase required for the same process.
      supported_by:
        - reference_id: PMID:30933966
          supporting_text: TMEM41B, is required for phagophore maturation.
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IMP
    original_reference_id: PMID:30093494
    review:
      summary: A genome-wide CRISPR screen identified the VMP1-related VTT-domain protein
        TMEM41B as required for autophagosome formation; VMP1 interacts with TMEM41B
        and is required for the same process.
      action: ACCEPT
      reason: Supports the core autophagosome assembly process for the VMP1/TMEM41B VTT-domain
        family. VMP1 and TMEM41B both contribute to autophagosome formation.
      supported_by:
        - reference_id: PMID:30093494
          supporting_text: Genome-wide CRISPR screen identifies TMEM41B as a gene required
            for autophagosome formation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30093494
    review:
      summary: This IPI records the experimentally validated VMP1-TMEM41B interaction.
      action: KEEP_AS_NON_CORE
      reason: Bare protein binding is uninformative as a molecular function, but the
        VMP1-TMEM41B interaction between the two cooperating ER scramblases is biologically
        meaningful. Kept as non-core supporting evidence.
      supported_by:
        - reference_id: PMID:30093494
          supporting_text: Genome-wide CRISPR screen identifies TMEM41B as a gene required
            for autophagosome formation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19056683
    review:
      summary: This IPI records the VMP1-TP53INP2 interaction, proposed to recruit LC3/GABARAP
        proteins to the autophagosome membrane.
      action: KEEP_AS_NON_CORE
      reason: Bare protein binding is uninformative as a molecular function, but the
        TP53INP2 interaction is experimentally supported and relevant to autophagy. Kept
        as non-core supporting evidence.
      supported_by:
        - reference_id: PMID:19056683
          supporting_text: TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related
            proteins to the autophagosome membrane by interacting with the transmembrane
            protein VMP1.
  - term:
      id: GO:0000421
      label: autophagosome membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Autophagosome membrane localization is inferred by sequence similarity
        to the mouse ortholog. VMP1 is primarily ER-resident and acts at ER-isolation
        membrane contacts.
      action: KEEP_AS_NON_CORE
      reason: VMP1's principal residence is the ER membrane; a stable autophagosome membrane
        pool is less well established for the mammalian protein. The interaction with
        TP53INP2 and isolation-membrane contacts provides some support, so retained as
        non-core rather than removed.
      supported_by:
        - reference_id: PMID:19056683
          supporting_text: TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related
            proteins to the autophagosome membrane by interacting with the transmembrane
            protein VMP1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17724469
    review:
      summary: This IPI records the VMP1-TJP1 (ZO-1) interaction reported in the cell-cell
        adhesion study.
      action: KEEP_AS_NON_CORE
      reason: Bare protein binding is uninformative as a molecular function, and the
        TJP1 interaction supports the peripheral adhesion role rather than the core ER
        scramblase function. Kept as non-core supporting evidence.
      supported_by:
        - reference_id: PMID:17724469
          supporting_text: It interacts with the tight junction protein Zonula Occludens-1
            and colocalizes in spots between neighboring HEK293 cells.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: PMID:17724469
    review:
      summary: Even in the cell-adhesion study, VMP1 was localized to the ER (in addition
        to a reported plasma-membrane pool).
      action: ACCEPT
      reason: ER localization is consistent with the established core site of VMP1; supported
        by IDA.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
  - term:
      id: GO:0034329
      label: cell junction assembly
    evidence_type: IMP
    original_reference_id: PMID:17724469
    review:
      summary: VMP1 knockdown disrupts tight junction formation and initial cell-cell
        contacts in this early study.
      action: KEEP_AS_NON_CORE
      reason: The junction/adhesion role rests on a single early study and is peripheral
        to the predominant ER scramblase function. Retained as non-core given the supporting
        IMP and interaction evidence.
      supported_by:
        - reference_id: PMID:17724469
          supporting_text: Vmp1 is a plasma membrane protein and an essential component
            of initial cell-cell contacts and tight junction formation.
  - term:
      id: GO:0098609
      label: cell-cell adhesion
    evidence_type: IMP
    original_reference_id: PMID:17724469
    review:
      summary: VMP1 downregulation causes loss of cell adherence and increased invasion,
        supporting a cell-cell adhesion role in this early study.
      action: KEEP_AS_NON_CORE
      reason: Cell-cell adhesion is supported by a single study and is not the core function;
        retained as non-core given the experimental (IMP) support.
      supported_by:
        - reference_id: PMID:17724469
          supporting_text: Downregulation of VMP1 by RNAi results in loss of cell adherence,
            and increases the invasion capacity of the non-invasive kidney cancer cell
            line Caki-2.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: GO_REF:0000054
    review:
      summary: Fluorescent fusion-protein localization (LIFEdb) places VMP1 at the endoplasmic
        reticulum.
      action: ACCEPT
      reason: Independent IDA evidence for ER localization, consistent with the core
        site of action.
      supported_by:
        - reference_id: PMID:28890335
          supporting_text: the ER-localized metazoan-specific autophagy protein EPG-3/VMP1
            controls ER-IM contacts.
core_functions:
  - description: Phospholipid scramblase that equilibrates phospholipids (PS, PE, PC)
      and cholesterol between the two leaflets of the ER membrane in an ATP- and calcium-independent
      manner
    supported_by:
      - reference_id: PMID:33929485
        supporting_text: TMEM41B and VMP1 are phospholipid scramblases whose deficiency
          impairs the normal cellular distribution of cholesterol and phosphatidylserine.
      - reference_id: PMID:33850023
        supporting_text: In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases.
    molecular_function:
      id: GO:0017128
      label: phospholipid scramblase activity
    directly_involved_in:
      - id: GO:0006869
        label: lipid transport
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
  - description: Required for early autophagosome formation, reequilibrating ER membrane
      leaflets as lipids are extracted by the lipid transfer protein ATG2 and controlling
      ER-isolation membrane contacts
    supported_by:
      - reference_id: PMID:28890335
        supporting_text: Loss of VMP1 causes stable association of IMs with the ER, thus
          blocking autophagosome formation.
      - reference_id: PMID:33850023
        supporting_text: TMEM41B and VMP1 reside in a complex on the ER and are necessary
          during autophagosome expansion
    molecular_function:
      id: GO:0017128
      label: phospholipid scramblase activity
    directly_involved_in:
      - id: GO:0000045
        label: autophagosome assembly
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
      - id: GO:0000407
        label: phagophore assembly site
  - description: Promotes SERCA (ATP2A) calcium-pump activity by competing with phospholamban
      and sarcolipin, thereby controlling ER membrane contact sites with isolation membranes,
      lipid droplets, mitochondria and endosomes
    supported_by:
      - reference_id: PMID:28890335
        supporting_text: VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN
          inhibitory complex.
    molecular_function:
      id: GO:0017128
      label: phospholipid scramblase activity
    directly_involved_in:
      - id: GO:1901896
        label: positive regulation of ATPase-coupled calcium transmembrane transporter
          activity
      - id: GO:0140056
        label: organelle localization by membrane tethering
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
  - description: Required for release of lipoproteins from the ER membrane into the ER
      lumen for secretion, downstream of its phospholipid scramblase activity
    supported_by:
      - reference_id: PMID:31526472
        supporting_text: the release of lipoproteins from the ER membrane requires VMP1
    molecular_function:
      id: GO:0017128
      label: phospholipid scramblase activity
    directly_involved_in:
      - id: GO:0042953
        label: lipoprotein transport
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
proposed_new_terms:
  - proposed_name: endoplasmic reticulum membrane phospholipid scrambling
    proposed_definition: The movement of phospholipids between the two leaflets of
      the endoplasmic reticulum membrane bilayer, mediated by a scramblase, to maintain
      or reequilibrate transbilayer lipid distribution.
    justification: The existing process annotation GO:0017121 plasma membrane phospholipid
      scrambling mislocalizes VMP1 scramblase activity to the plasma membrane. A process
      term scoped to the ER membrane would more accurately capture where VMP1 (and TMEM41B)
      scramble phospholipids.
    supported_by:
      - reference_id: PMID:33850023
        supporting_text: scramblases that reequilibrate the leaflets of donor and acceptor
          organelle membranes as lipids are depleted or augmented
suggested_questions:
  - question: Does VMP1 scramblase activity have any intrinsic headgroup or sterol selectivity
      in a native ER lipid environment, given that in vitro assays show little specificity?
  - question: How is VMP1 scramblase activity spatially and temporally regulated (e.g.
      by palmitoylation, the SERCA/calcium axis, or partner proteins) to coordinate autophagy,
      lipoprotein secretion and lipid droplet biogenesis?
suggested_experiments:
  - description: Structure-guided mutagenesis of the VTT/DedA reentrant-loop residues
      to separate scramblase activity from SERCA regulation, followed by rescue of autophagosome
      formation, lipoprotein secretion and PS/cholesterol distribution defects in VMP1-knockout
      cells.
  - description: Reconstitution of VMP1 with ATG2A and ATG9A on donor/acceptor liposomes
      to quantitatively test the proposed lipid-transfer-plus-scramblase model of autophagosome
      membrane expansion.
  - description: Cryo-EM determination of the human VMP1 structure (alone and with ATG2A)
      to define the transbilayer lipid-conduction pathway.
status: COMPLETE