Ctns (CG17119) encodes Drosophila cystinosin (dCTNS), a seven-transmembrane PQ-loop protein of the lysosomal membrane and the fly member of the cystinosin subfamily that includes human CTNS and yeast ERS1. It exports cystine, the disulfide-linked dimer of cysteine, from the lysosomal lumen to the cytosol; by analogy with human cystinosin this efflux is proton-coupled. In the larval fat body, cystine released from lysosomes during fasting replenishes cytosolic cysteine, which feeds coenzyme A synthesis and acetyl-CoA, the TCA cycle and other amino acid metabolism. Loss of Ctns causes cystine accumulation, lower cysteine levels during fasting, increased TORC1 reactivation with failure to maintain autophagy, developmental delay on a low-protein diet and reduced survival under starvation; these effects on TORC1 signalling and growth are downstream consequences of the transport activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003333 amino acid transmembrane transport | ISS PMID:17443808 A screen for neurotransmitter transporters expressed in the ... | MODIFY | Summary: Amino acid transmembrane transport is true but too broad; the substrate and route are lysosomal cystine export. Reason: The process is correct for a cystine exporter, but the specific term GO:1904919 (a descendant of GO:0003333, already carried by Ctns from IMP) is supported by fly mutant cystine accumulation, cysteamine bypass, and orthology to human CTNS. The With/From of this ISS row (Eaat1) is not a homolog of Ctns; see source_defects. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes file:DROME/Ctns/Ctns-bioinformatics/RESULTS-rereview.md Ctns and human CTNS share the PQ-loop Pfam domain PF04193 and the same PANTHER subfamily PTHR13131:SF5 (CYSTINOSIN) |
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Cystinosin acts in the lysosomal membrane. Reason: Endogenous tagging places dCTNS specifically on fly fat-body lysosomes, the mutant cystine accumulation and cysteamine bypass tie this compartment to its transport function, and human CTNS in the same PANTHER subfamily (PTHR13131:SF5) is an experimentally characterised lysosomal membrane cystine exporter. The IBA places this at a PTHR13131 node that includes the fly gene; Ctns appears among its own descendant evidence, which is expected. Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Cystinosin acts in the lysosomal membrane. Reason: Endogenous tagging places dCTNS specifically on fly fat-body lysosomes, the mutant cystine accumulation and cysteamine bypass tie this compartment to its transport function, and human CTNS in the same PANTHER subfamily (PTHR13131:SF5) is an experimentally characterised lysosomal membrane cystine exporter. The electronic row agrees with the experimental localization. Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IMP PMID:35175796 Lysosomal cystine mobilization shapes the response of TORC1 ... | ACCEPT | Summary: Cystinosin acts in the lysosomal membrane. Reason: Endogenous tagging places dCTNS specifically on fly fat-body lysosomes, the mutant cystine accumulation and cysteamine bypass tie this compartment to its transport function, and human CTNS in the same PANTHER subfamily (PTHR13131:SF5) is an experimentally characterised lysosomal membrane cystine exporter. The localization was assayed directly by endogenous tagging, so IDA would be the more fitting evidence code (see source_defects). Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Cystinosin acts in the lysosomal membrane. Reason: Endogenous tagging places dCTNS specifically on fly fat-body lysosomes, the mutant cystine accumulation and cysteamine bypass tie this compartment to its transport function, and human CTNS in the same PANTHER subfamily (PTHR13131:SF5) is an experimentally characterised lysosomal membrane cystine exporter. The ISS donor O60931 is an in-subfamily ortholog. Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes file:DROME/Ctns/Ctns-bioinformatics/RESULTS-rereview.md Ctns and human CTNS share the PQ-loop Pfam domain PF04193 and the same PANTHER subfamily PTHR13131:SF5 (CYSTINOSIN) |
| GO:0015171 amino acid transmembrane transporter activity | ISS PMID:17443808 A screen for neurotransmitter transporters expressed in the ... | MODIFY | Summary: Amino acid transporter activity is true but too broad; the established substrate is L-cystine. Reason: Ctns transports cystine; the specific child term GO:0015184 L-cystine transmembrane transporter activity is already carried by Ctns (IBA, IMP, ISS) and is supported by fly mutant cystine accumulation, cysteamine bypass and orthology to the experimentally characterised H+-driven human CTNS. The With/From of this ISS row (Eaat1) is not a homolog of Ctns; see source_defects. Proposed replacements: L-cystine transmembrane transporter activity Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes file:DROME/Ctns/Ctns-bioinformatics/RESULTS-rereview.md Ctns and human CTNS share the PQ-loop Pfam domain PF04193 and the same PANTHER subfamily PTHR13131:SF5 (CYSTINOSIN) |
| GO:0015179 L-amino acid transmembrane transporter activity | IEA GO_REF:0000117 | MODIFY | Summary: L-amino acid transporter activity is true but too broad; the substrate is L-cystine. Reason: The ARBA-derived term is a correct ancestor of GO:0015184 L-cystine transmembrane transporter activity, which Ctns already carries and which the fly and orthology evidence supports. No evidence indicates transport of other L-amino acids. Proposed replacements: L-cystine transmembrane transporter activity Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0015184 L-cystine transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Lysosomal cystine export is the core transporter activity. Reason: Cystine accumulation in dCTNS mutants, rescue of the starvation phenotype by cysteamine (which exports lysosomal cystine independently of cystinosin), and membership of PANTHER subfamily PTHR13131:SF5 with human CTNS, whose H+-driven lysosomal cystine export was shown directly, establish cystine transport as the core activity. Transport has not been measured biochemically for the fly protein itself. The PAINT node spans human, mouse, yeast ERS1 and fly cystinosins; Ctns among the donors reflects its own experimental annotation. Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0015184 L-cystine transmembrane transporter activity | IMP PMID:35175796 Lysosomal cystine mobilization shapes the response of TORC1 ... | ACCEPT | Summary: Lysosomal cystine export is the core transporter activity. Reason: Cystine accumulation in dCTNS mutants, rescue of the starvation phenotype by cysteamine (which exports lysosomal cystine independently of cystinosin), and membership of PANTHER subfamily PTHR13131:SF5 with human CTNS, whose H+-driven lysosomal cystine export was shown directly, establish cystine transport as the core activity. Transport has not been measured biochemically for the fly protein itself. Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0015184 L-cystine transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Lysosomal cystine export is the core transporter activity. Reason: Cystine accumulation in dCTNS mutants, rescue of the starvation phenotype by cysteamine (which exports lysosomal cystine independently of cystinosin), and membership of PANTHER subfamily PTHR13131:SF5 with human CTNS, whose H+-driven lysosomal cystine export was shown directly, establish cystine transport as the core activity. Transport has not been measured biochemically for the fly protein itself. Supporting Evidence: PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes file:DROME/Ctns/Ctns-bioinformatics/RESULTS-rereview.md Ctns and human CTNS share the PQ-loop Pfam domain PF04193 and the same PANTHER subfamily PTHR13131:SF5 (CYSTINOSIN) |
| GO:0015811 L-cystine transport | ISS GO_REF:0000024 | MODIFY | Summary: L-cystine transport is correct but less specific than the supported lysosome-to-cytosol export term. Reason: GO:1904919 L-cystine transmembrane transport from lysosomal lumen to cytosol is a descendant of GO:0015811, is already carried by Ctns (IMP, IEA), and is supported by the lysosomal localization, mutant cystine accumulation, cysteamine bypass and the in-subfamily human ortholog. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:35175796 dCTNS−/− larvae showed accumulation of cystine file:DROME/Ctns/Ctns-bioinformatics/RESULTS-rereview.md Ctns and human CTNS share the PQ-loop Pfam domain PF04193 and the same PANTHER subfamily PTHR13131:SF5 (CYSTINOSIN) |
| GO:0034486 vacuolar transmembrane transport | IBA GO_REF:0000033 | MODIFY | Summary: Vacuolar transmembrane transport is a correct but broad parent of lysosomal cystine export. Reason: The PAINT node covering animal cystinosins and yeast ERS1 justifies a vacuolar/lysosomal transport process for the subfamily; for the fly gene the more specific descendant GO:1904919, already carried by Ctns, is supported directly. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000319795 SUPPORTS TRANSFER Cystinosin node spanning animal CTNS orthologs and yeast ERS1; Ctns is inside the clade (PTHR13131:SF5). The transfer is sound; the propagated term is only broader than what the fly evidence supports. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:35175796 dCTNS−/− larvae showed accumulation of cystine |
| GO:1904919 L-cystine transmembrane transport from lysosomal lumen to cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: The transporter mobilizes cystine from the lysosomal lumen into the cytosol. Reason: Lysosomal localization, cystine accumulation in mutants and cysteamine bypass of the starvation phenotype establish that dCTNS moves cystine out of the lysosome into the cytosol, where it supplies cysteine for CoA and other metabolism during fasting. The direction matches the H+-driven export shown for human CTNS in the same PANTHER subfamily. Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] |
| GO:1904919 L-cystine transmembrane transport from lysosomal lumen to cytosol | IMP PMID:35175796 Lysosomal cystine mobilization shapes the response of TORC1 ... | ACCEPT | Summary: The transporter mobilizes cystine from the lysosomal lumen into the cytosol. Reason: Lysosomal localization, cystine accumulation in mutants and cysteamine bypass of the starvation phenotype establish that dCTNS moves cystine out of the lysosome into the cytosol, where it supplies cysteine for CoA and other metabolism during fasting. The direction matches the H+-driven export shown for human CTNS in the same PANTHER subfamily. Supporting Evidence: PMID:35175796 Endogenous tagging of the Drosophila ortholog CG17119 (hereafter referred to as dCTNS) confirmed its specific lysosomal localization in cells of the fat body PMID:35175796 The role of dCTNS during starvation was dependent on its cystine transport function PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:35175796 dCTNS−/− larvae showed accumulation of cystine PMID:35175796 cysteamine [which facilitates cystine export out of the lysosome independently of cystinosin (21)] |
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Download this section (compressed HTML)Q: Is cystine efflux by Drosophila dCTNS proton-coupled like human cystinosin, and does it share the human protein's apparent selectivity for cystine over other lysosomal amino acids?
Q: Does dCTNS influence TORC1 only through cysteine supply, or does it also interact with the lysosomal TORC1 machinery as has been proposed for mammalian cystinosin?
Experiment: Express dCTNS with its lysosomal sorting signal removed at the plasma membrane of cultured cells or Xenopus oocytes and measure radiolabelled L-cystine uptake at acidic versus neutral pH, with other amino acids as competitors, to test transport, proton coupling and substrate selectivity directly.
Type: heterologous transport assay
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