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.
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.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: VMP1 is an ER-resident multi-pass membrane protein; ER localization is the well-established core site of action. 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. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | ACCEPT | Summary: VMP1 is a component of the endomembrane system, consistent with its ER/ERGIC/vacuole membrane localization. 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. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum |
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: VMP1 is required for early autophagosome formation, reequilibrating ER membrane leaflets as lipids are extracted by ATG2; this is a core biological process. 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. Supporting Evidence: PMID:28890335 Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. PMID:33850023 TMEM41B and VMP1 reside in a complex on the ER and are necessary during autophagosome expansion |
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: VMP1 is an integral multi-pass membrane protein; the bare membrane term is correct but very general. 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. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum |
| GO:0007030 Golgi organization | IBA GO_REF:0000033 | KEEP AS NON CORE | 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). 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. Supporting Evidence: file:human/VMP1/VMP1-deep-research-falcon.md VMP1 is a core ER scramblase that underpins autophagosome membrane biogenesis by cooperating with ATG2 and ATG9 |
| GO:0005774 vacuolar membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane is the core site of VMP1 action and is well supported experimentally. 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. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:17724469 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. |
| GO:0006869 lipid transport | IEA GO_REF:0000043 | ACCEPT | 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. 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. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. |
| GO:0006914 autophagy | IEA GO_REF:0000120 | ACCEPT | Summary: VMP1 is a core autophagy protein required for autophagosome formation. 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. Supporting Evidence: PMID:28890335 Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. |
| GO:0007155 cell adhesion | IEA GO_REF:0000043 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:17724469 our findings establish Vmp1 to be a novel cell-cell adhesion protein |
| GO:0017121 plasma membrane phospholipid scrambling | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:33850023 TMEM41B and VMP1 reside in a complex on the ER and are necessary during autophagosome expansion |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: This by-similarity location is plausible and consistent with VMP1 biology but is less central than the ER membrane. Retained as non-core. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum |
| GO:0005515 protein binding | IPI PMID:23316280 The VMP1-Beclin 1 interaction regulates autophagy induction. | ACCEPT | Summary: This IPI captures the VMP1-Beclin 1 (BECN1) interaction that recruits/activates the class III PI3K complex during autophagy induction. 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. Supporting Evidence: PMID:23316280 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 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Protein binding from a high-throughput binary (Y2H) interactome map (interactors including CYB5R3, FAM209A, MEOX2, SLC39A9, ERGIC3). 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Protein binding from a large-scale affinity-purification interactome (e.g. VMP1-ERGIC3). Reason: Generic protein binding from a high-throughput proteomic network is uninformative as a molecular function. Retained as non-core supporting evidence. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0000407 phagophore assembly site | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: PMID:28890335 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. |
| GO:0007566 embryo implantation | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/VMP1/VMP1-deep-research-falcon.md VMP1 is broadly required for ER-derived membrane remodeling, including lipid droplets, lipoproteins, and viral DMVs |
| GO:0042953 lipoprotein transport | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: PMID:31526472 the release of lipoproteins from the ER membrane requires VMP1 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) curation places VMP1 at the endoplasmic reticulum. Reason: Direct immunofluorescence localization to the ER agrees with the established core site of VMP1 action. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:33850023 A model for a partnership of lipid transfer proteins and scr... | ACCEPT | Summary: Purified VMP1 reconstituted into liposomes scrambles phospholipids (NBD-PE, NBD-PC) between bilayer leaflets; this is the core molecular function of VMP1. Reason: Direct in vitro reconstitution demonstrates VMP1 is a phospholipid scramblase. This is the central, mechanistically defining molecular function of the protein. Supporting Evidence: PMID:33850023 In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases. PMID:33850023 both NBD-PE and NBD-phosphatidylcholine (PC) are substrates |
| GO:0017128 phospholipid scramblase activity | IDA PMID:33929485 TMEM41B and VMP1 are scramblases and regulate the distributi... | ACCEPT | Summary: Independent reconstitution shows purified VMP1 scrambles NBD-PE, PC and PS in an ATP- and calcium-independent, headgroup-nonspecific manner. 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. Supporting Evidence: PMID:33929485 TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. PMID:33929485 The scramblase activity of TMEM41B/VMP1 did not depend on ATP and was not affected by calcium |
| GO:0042953 lipoprotein transport | IMP PMID:31526472 A critical role of VMP1 in lipoprotein secretion. | ACCEPT | Summary: Loss-of-function of VMP1 (zebrafish, mouse, cells) blocks release of lipoproteins from the ER membrane into the ER lumen, causing lipid accumulation. Reason: Strong genetic/IMP evidence across organisms establishes VMP1 as required for lipoprotein secretion, downstream of its scramblase activity. A genuine core-related process. Supporting Evidence: PMID:31526472 Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein accumulation in the intestine and liver. |
| GO:0016240 autophagosome membrane docking | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: VMP1 controls the dynamic contact (docking/undocking) between isolation membranes and the ER; its loss locks isolation membranes onto the ER. 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. Supporting Evidence: PMID:28890335 Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. |
| GO:0140056 organelle localization by membrane tethering | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | 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. 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. Supporting Evidence: PMID:28890335 VMP1 also modulates ER contacts with lipid droplets, mitochondria, and endosomes. |
| GO:1990456 mitochondrion-endoplasmic reticulum membrane tethering | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: VMP1 modulates ER-mitochondria contacts as part of its SERCA/calcium-dependent control of ER membrane contact sites. Reason: The study directly shows VMP1 modulates ER-mitochondria contacts; this specific tethering term is supported. Supporting Evidence: PMID:28890335 VMP1 also modulates ER contacts with lipid droplets, mitochondria, and endosomes. |
| GO:0000045 autophagosome assembly | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: VMP1 is required for autophagosome formation; its loss blocks autophagosome formation by trapping isolation membranes on the ER. Reason: Direct experimental evidence (IDA) for the core autophagosome assembly process. Duplicate of the IBA term with experimental support. Supporting Evidence: PMID:28890335 Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. |
| GO:0005515 protein binding | IPI PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | KEEP AS NON CORE | Summary: This IPI captures the experimentally validated VMP1 interactions with SERCA (ATP2A1/2/3), PLN and SLN that underlie VMP1 control of SERCA activity. 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. Supporting Evidence: PMID:28890335 VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: Direct evidence places VMP1 on the ER membrane, its core site of action. Reason: IDA-supported ER membrane localization; the most informative and accurate cellular component for VMP1. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
| GO:0006914 autophagy | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: VMP1 is directly required for autophagy/autophagosome formation. Reason: Direct experimental support for autophagy; consistent with the core role, with the more specific autophagosome assembly term also annotated. Supporting Evidence: PMID:28890335 Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. |
| GO:1901896 positive regulation of ATPase-coupled calcium transmembrane transporter activity | IDA PMID:28890335 The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates ... | ACCEPT | Summary: VMP1 promotes SERCA (ATP2A) calcium-pump activity by competing with PLN and SLN, preventing the inhibitory SERCA/PLN/SLN complex. Reason: Directly supported molecular-level regulatory function; VMP1 activation of SERCA is the mechanism by which it controls ER membrane contact sites. Supporting Evidence: PMID:28890335 VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex. |
| GO:0000045 autophagosome assembly | IMP PMID:30933966 CRISPR screening using an expanded toolkit of autophagy repo... | ACCEPT | Summary: CRISPR screening of autophagy reporters identifies the VTT-domain ER proteins (TMEM41B, with VMP1 as paralog) as required for phagophore maturation/autophagosome formation. 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. Supporting Evidence: PMID:30933966 TMEM41B, is required for phagophore maturation. |
| GO:0000045 autophagosome assembly | IMP PMID:30093494 Genome-wide CRISPR screen identifies TMEM41B as a gene requi... | ACCEPT | 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. Reason: Supports the core autophagosome assembly process for the VMP1/TMEM41B VTT-domain family. VMP1 and TMEM41B both contribute to autophagosome formation. Supporting Evidence: PMID:30093494 Genome-wide CRISPR screen identifies TMEM41B as a gene required for autophagosome formation. |
| GO:0005515 protein binding | IPI PMID:30093494 Genome-wide CRISPR screen identifies TMEM41B as a gene requi... | KEEP AS NON CORE | Summary: This IPI records the experimentally validated VMP1-TMEM41B interaction. 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. Supporting Evidence: PMID:30093494 Genome-wide CRISPR screen identifies TMEM41B as a gene required for autophagosome formation. |
| GO:0005515 protein binding | IPI PMID:19056683 The TP53INP2 protein is required for autophagy in mammalian ... | KEEP AS NON CORE | Summary: This IPI records the VMP1-TP53INP2 interaction, proposed to recruit LC3/GABARAP proteins to the autophagosome membrane. 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. Supporting Evidence: PMID:19056683 TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related proteins to the autophagosome membrane by interacting with the transmembrane protein VMP1. |
| GO:0000421 autophagosome membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:19056683 TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related proteins to the autophagosome membrane by interacting with the transmembrane protein VMP1. |
| GO:0005515 protein binding | IPI PMID:17724469 Reduced expression of vacuole membrane protein 1 affects the... | KEEP AS NON CORE | Summary: This IPI records the VMP1-TJP1 (ZO-1) interaction reported in the cell-cell adhesion study. 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. Supporting Evidence: PMID:17724469 It interacts with the tight junction protein Zonula Occludens-1 and colocalizes in spots between neighboring HEK293 cells. |
| GO:0005783 endoplasmic reticulum | IDA PMID:17724469 Reduced expression of vacuole membrane protein 1 affects the... | ACCEPT | Summary: Even in the cell-adhesion study, VMP1 was localized to the ER (in addition to a reported plasma-membrane pool). Reason: ER localization is consistent with the established core site of VMP1; supported by IDA. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
| GO:0034329 cell junction assembly | IMP PMID:17724469 Reduced expression of vacuole membrane protein 1 affects the... | KEEP AS NON CORE | Summary: VMP1 knockdown disrupts tight junction formation and initial cell-cell contacts in this early study. 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. Supporting Evidence: PMID:17724469 Vmp1 is a plasma membrane protein and an essential component of initial cell-cell contacts and tight junction formation. |
| GO:0098609 cell-cell adhesion | IMP PMID:17724469 Reduced expression of vacuole membrane protein 1 affects the... | KEEP AS NON CORE | Summary: VMP1 downregulation causes loss of cell adherence and increased invasion, supporting a cell-cell adhesion role in this early study. 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. Supporting Evidence: PMID:17724469 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. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | ACCEPT | Summary: Fluorescent fusion-protein localization (LIFEdb) places VMP1 at the endoplasmic reticulum. Reason: Independent IDA evidence for ER localization, consistent with the core site of action. Supporting Evidence: PMID:28890335 the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: Cryo-EM determination of the human VMP1 structure (alone and with ATG2A) to define the transbilayer lipid-conduction pathway.
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