Tango5, also called Vmp1, is the Drosophila member of the VMP1 subfamily of DedA/VTT-domain multipass membrane proteins and is the ortholog of human VMP1 (PANTHER PTHR10281:SF1). The gene encodes a longer and a shorter protein that differ only by a disordered N-terminal extension. The UniProt entry Q7KVQ7 is the shorter form, which starts at the internal Met103 of the 530-residue product. Endogenously tagged Vmp1 resides in the endoplasmic reticulum membrane. By orthology to VMP1, whose reconstituted protein is an ATP- and calcium-independent phospholipid scramblase, Tango5 is inferred to equilibrate phospholipids between the two leaflets of the ER membrane. In flies Vmp1 is essential for viability. It is required for autophagosome formation and autophagic flux in the larval intestine, and acts genetically upstream of Vps13D and Marf in clearing mitochondria and limiting mitochondria-ER contact. An RNAi screen in S2 cells also found that its depletion impairs constitutive secretion and causes Golgi membranes to fuse with the ER.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular function ND annotation: when it was made, no molecular function had been curated for this gene product from literature. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the molecular function is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. Re-checked 2026-10-31: the scramblase assays cited in core_functions are on human VMP1 (PMID:33929485); the Drosophila study (PMID:34019822) is genetic and does not assay the activity. The term the earlier MODIFY proposed, phospholipid scramblase activity, is kept as its own NEW row. The gene's own literature-search record finds no study of this gene product in this species that identifies a molecular function. Supporting Evidence: file:DROME/Tango5/Tango5-deep-research-falcon.md VMP1 has been biochemically reconstituted as a scramblase, but Q7KVQ7/Tango5 has not been assayed directly. |
| GO:0005774 vacuolar membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: The vacuolar-membrane location comes from the historical family name, not from any localization of the fly protein. Reason: The UniProt SubCell line behind this row is an ARBA prediction. It traces to the name "vacuole membrane protein 1", which was given to the rodent protein because it is induced during pancreatitis-associated vacuolization. Endogenously GFP-tagged fly Vmp1 co-localizes with the ER markers Sec61beta and SERCA, and no fly data place it on vacuoles or lysosomes. A minor endolysosomal pool cannot be excluded, but this term overstates what is known. Supporting Evidence: PMID:34019822 GFP-Vmp1 co-localizes with the ER markers Sec61Ξ² and SERCA in intestine cells |
| GO:0005783 endoplasmic reticulum | IDA PMID:16452979 Functional genomics reveals genes involved in protein secret... | MODIFY | Summary: Tango5 is in the ER, and more precisely it is an integral ER membrane protein. Reason: The direct-assay ER localization from the Bard et al. secretion screen is correct. It is confirmed by the co-localization of endogenous GFP-Vmp1 with Sec61beta and SERCA in fly intestine. Tango5 is a multipass protein with an intact VMP1/DedA membrane core, so the specific supported location is the ER membrane (GO:0005789), which is where the inferred scramblase acts. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:34019822 GFP-Vmp1 co-localizes with the ER markers Sec61Ξ² and SERCA in intestine cells file:genes/DROME/Tango5/Tango5-flybase.txt located_in endoplasmic reticulum inferred from direct assay file:DROME/Tango5/Tango5-uniprot.txt FT TRANSMEM 69..86 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | MODIFY | Summary: The ER location is correct, and the more precise supported term is ER membrane. Reason: This electronic row makes the same claim as the IDA row and gets the same action. The ER localization is confirmed experimentally in fly, and the protein is an integral multipass ER protein, so the specific term is endoplasmic reticulum membrane. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:34019822 GFP-Vmp1 co-localizes with the ER markers Sec61Ξ² and SERCA in intestine cells |
| GO:0007030 Golgi organization | IMP PMID:16452979 Functional genomics reveals genes involved in protein secret... | KEEP AS NON CORE | Summary: In S2 cells, Tango5 depletion causes Golgi membranes to fuse with the ER. The phenotype is genuine but probably secondary to its ER membrane role. Reason: Bard et al. classified Tango5 among the screen genes whose depletion redistributes Golgi membranes into the ER (more than 50% of treated cells, according to FlyBase curation of the full text). A PAINT curator also propagated Golgi organization at PTN000031591, using the fly experimental annotation as a donor. The protein resides in the ER and is inferred to scramble lipids there, so its effect on Golgi integrity is best viewed as a consequence of ER membrane homeostasis rather than a core activity. Only the abstract is cached, so I defer to the curator on the phenotype. Supporting Evidence: PMID:16452979 Here we show that depletion of class A genes redistributes Golgi membranes into the endoplasmic reticulum file:genes/DROME/Tango5/Tango5-flybase.txt results in fusion of Golgi membranes with the endoplasmic reticulum in more than 50% of the treated cells |
| GO:0009306 protein secretion | IMP PMID:16452979 Functional genomics reveals genes involved in protein secret... | KEEP AS NON CORE | Summary: Tango5 is required for constitutive secretion in S2 cells. This is a screen-level phenotype that is probably an indirect effect. Reason: The genome-wide RNAi screen identified Tango5 as needed for constitutive secretion, and the experimental annotation stands. However, the evidence is necessity in a screen. When the PAINT curator placed the gene's other experimental process (Golgi organization) on the VMP1 node, protein secretion was not propagated, which I treat as a deliberate decision. The likely mechanism is indirect, through ER membrane lipid homeostasis and Golgi integrity, so the row is kept as non-core. Supporting Evidence: PMID:16452979 We performed a genome-wide RNA-mediated interference screen in a Drosophila cell line to identify genes required for constitutive protein secretion. file:genes/DROME/Tango5/Tango5-flybase.txt dsRNA directed against Tango5 inhibits protein secretion in S2 cells |
| GO:0017128 phospholipid scramblase activity | ISS PMID:33929485 TMEM41B and VMP1 are scramblases and regulate the distributi... | NEW | Summary: Inferred phospholipid scramblase activity for this gene product, proposed during the NO_DATA re-action pass. Reason: Phospholipid scramblase activity is inferred for this gene product (ISS), not shown for it experimentally; the ND row for the aspect therefore stays (projects/NO_DATA.md). Since then, reconstitution of human VMP1 has established phospholipid scramblase activity. A PAINT curator placed that function at PTN000031590, a node whose descendants include the fly Tango5 product Q9W2S1, which is in the same PANTHER subfamily (PTHR10281:SF1) as VMP1. Supporting Evidence: PMID:33929485 Together, these data indicate that both TMEM41B and VMP1 are scramblases. file:DROME/Tango5/Tango5-bioinformatics/RESULTS.md PANTHER: Q7KVQ7, Q9W2S1 and human VMP1 (Q96GC9) are all placed in PTHR10281:SF1 VACUOLE MEMBRANE PROTEIN 1. |
| GO:0000045 autophagosome assembly | IMP PMID:34019822 Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway ... | NEW | Summary: Vmp1/Tango5 is required for autophagosome formation in the larval intestine. Reason: In fly intestine cells, vmp1 RNAi blocks mCherry-Atg8a puncta formation and vmp1 null cells accumulate the cargo receptor Ref2p, showing a block in autophagosome formation. This is not only necessity evidence. Tango5 itself is thought to do part of the work, as the ER phospholipid scramblase that supplies lipid for phagophore expansion. The scramblase activity is shown for human VMP1 and inferred for Tango5 in the separate NEW ISS row for GO:0017128. Comparator check, human VMP1 carries autophagosome assembly by IDA and IMP. The gene carries no ancestor or descendant of this term, and the review already lists it as a core process. Supporting Evidence: PMID:34019822 cells with reduced Vmp1 function that express vmp1 RNAi and green fluorescent protein (GFP) did not accumulate mCherryAtg8a autophagy reporter puncta PMID:34019822 intestines with homozygous vmp1(Ξ) mutant cells lacking red fluorescent protein (RFP) accumulated the autophagic cargo receptor Ref2p (p62 in mammals) compared to neighboring control cells that possess RFP (Figure 1C and D), indicating that autophagy is impaired. PMID:33850023 In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases. |
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Download this section (compressed HTML)Q: Does purified Drosophila Tango5, in either the short (Q7KVQ7) or the long (Q9W2S1) form, scramble phospholipids in proteoliposomes, and does the disordered N-terminal extension of the long form have any function?
Q: Is the increased mitochondria-ER contact seen in vmp1-depleted fly cells due to excess contact formation or to a failure to disassemble contacts, and does it require scramblase activity?
Q: Are the secretion and Golgi-ER fusion phenotypes from the S2 screen direct consequences of loss of ER lipid scrambling, or secondary to impaired autophagy or ER stress?
Experiment: Reconstitute purified Tango5 isoforms in NBD-lipid proteoliposomes to measure scramblase activity, and test rescue of vmp1(delta) lethality and autophagy with scramblase-dead point mutants in the conserved VTT core.
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