CTNS encodes cystinosin, a seven-transmembrane PQ-loop family transporter of the lysosomal membrane that exports L-cystine, generated by lysosomal proteolysis, from the lysosomal lumen to the cytosol by proton symport, coupling cystine binding to protonation of a buried aspartate. Lysosomal sorting depends on a C-terminal GYDQL motif recognised by AP-3 and a second conformational motif; an alternatively spliced isoform (cystinosin-LKG) lacking GYDQL also reaches the plasma membrane. Cystinosin is also present in melanosomes and engages the Ragulator-Rag complex, linking lysosomal amino acid efflux to mTORC1 signalling. Biallelic loss of CTNS causes cystinosis, with intralysosomal cystine accumulation that damages kidney (renal Fanconi syndrome), eye and other organs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005764 lysosome | IDA PMID:11855931 Expression of CTNS alleles: subcellular localization and ami... | ACCEPT | Summary: Cystinosin is a lysosomal protein. Reason: Correct; lysosomal membrane is the more precise compartment. Supporting Evidence: PMID:12138135 cystinosin localized to tubule epithelia in three normal human kidneys, with a pattern similar to that of lysosome-associated membrane protein 2 PMID:11855931 The normal CTNS protein fused with either N- or C-terminal GFP colocalized with Lysotracker red PMID:15128704 Most of the mutations did not alter the lysosomal localization of cystinosin |
| GO:0005764 lysosome | IDA PMID:12138135 Immunolocalization of cystinosin, the protein defective in c... | ACCEPT | Summary: Cystinosin is a lysosomal protein. Reason: Correct; lysosomal membrane is the more precise compartment. Supporting Evidence: PMID:12138135 cystinosin localized to tubule epithelia in three normal human kidneys, with a pattern similar to that of lysosome-associated membrane protein 2 PMID:11855931 The normal CTNS protein fused with either N- or C-terminal GFP colocalized with Lysotracker red PMID:15128704 Most of the mutations did not alter the lysosomal localization of cystinosin |
| GO:0005764 lysosome | IDA PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: Cystinosin is a lysosomal protein. Reason: Correct; lysosomal membrane is the more precise compartment. Supporting Evidence: PMID:12138135 cystinosin localized to tubule epithelia in three normal human kidneys, with a pattern similar to that of lysosome-associated membrane protein 2 PMID:11855931 The normal CTNS protein fused with either N- or C-terminal GFP colocalized with Lysotracker red PMID:15128704 Most of the mutations did not alter the lysosomal localization of cystinosin |
| GO:0005764 lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: Cystinosin is a lysosomal protein. Reason: Correct; lysosomal membrane is the more precise compartment. Supporting Evidence: PMID:12138135 cystinosin localized to tubule epithelia in three normal human kidneys, with a pattern similar to that of lysosome-associated membrane protein 2 PMID:11855931 The normal CTNS protein fused with either N- or C-terminal GFP colocalized with Lysotracker red PMID:15128704 Most of the mutations did not alter the lysosomal localization of cystinosin |
| GO:0005765 lysosomal membrane | EXP PMID:18337546 Identification and subcellular localization of a new cystino... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | EXP PMID:25753619 Lysosomal Targeting of Cystinosin Requires AP-3. | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | EXP PMID:27148969 Carboxyl-Terminal SSLKG Motif of the Human Cystinosin-LKG Pl... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | EXP PMID:28082515 Impact of Cystinosin Glycosylation on Protein Stability by D... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IDA PMID:11150305 The targeting of cystinosin to the lysosomal membrane requir... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IDA PMID:11689434 Cystinosin, the protein defective in cystinosis, is a H(+)-d... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | IDA PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. 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 is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | NAS PMID:9537412 A novel gene encoding an integral membrane protein is mutate... | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-5340130 | ACCEPT | Summary: Cystinosin is an integral protein of the lysosomal membrane. Reason: Multiple independent localisation studies (GFP fusions, antisera, kidney immunostaining) place cystinosin in the lysosomal membrane, where it exports cystine. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0005769 early endosome | IDA NOT PMID:11150305 The targeting of cystinosin to the lysosomal membrane requir... | ACCEPT | Summary: NOT early endosome: wild-type cystinosin is targeted to lysosomes rather than residing in early endosomes. Reason: The negative annotation from the targeting-motif study is consistent with a direct AP-3-dependent intracellular route to lysosomes; we defer to the curator who read the full text. Supporting Evidence: PMID:11150305 showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes PMID:25753619 the tyrosine-based motif of cystinosin is a 'strong' AP-3 interacting motif responsible for lysosomal targeting of cystinosin by a direct intracellular pathway |
| GO:0005770 late endosome | IDA PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | KEEP AS NON CORE | Summary: Some cystinosin (including mislocalising mutants) is detected in late endosomes. Reason: Late endosomes lie on the route to lysosomes; this is a minor location. Supporting Evidence: PMID:15128704 Most of the mutations did not alter the lysosomal localization of cystinosin |
| GO:0005886 plasma membrane | EXP PMID:18337546 Identification and subcellular localization of a new cystino... | KEEP AS NON CORE | Summary: The cystinosin-LKG splice isoform is partly at the plasma membrane. Reason: Plasma membrane localisation is isoform-specific (cystinosin-LKG lacks the GYDQL lysosomal motif); the canonical isoform is lysosomal. Supporting Evidence: PMID:18337546 cystinosin-LKG is expressed in the plasma membrane, in lysosomes, and in other cytosolic structures PMID:27148969 the carboxyl-terminal SSLKG sequence of cystinosin-LKG is an important sorting motif that is required for efficient targeting the protein to the plasma membrane |
| GO:0005886 plasma membrane | EXP PMID:27148969 Carboxyl-Terminal SSLKG Motif of the Human Cystinosin-LKG Pl... | KEEP AS NON CORE | Summary: The cystinosin-LKG splice isoform is partly at the plasma membrane. Reason: Plasma membrane localisation is isoform-specific (cystinosin-LKG lacks the GYDQL lysosomal motif); the canonical isoform is lysosomal. Supporting Evidence: PMID:18337546 cystinosin-LKG is expressed in the plasma membrane, in lysosomes, and in other cytosolic structures PMID:27148969 the carboxyl-terminal SSLKG sequence of cystinosin-LKG is an important sorting motif that is required for efficient targeting the protein to the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The cystinosin-LKG splice isoform is partly at the plasma membrane. Reason: Plasma membrane localisation is isoform-specific (cystinosin-LKG lacks the GYDQL lysosomal motif); the canonical isoform is lysosomal. Supporting Evidence: PMID:18337546 cystinosin-LKG is expressed in the plasma membrane, in lysosomes, and in other cytosolic structures PMID:27148969 the carboxyl-terminal SSLKG sequence of cystinosin-LKG is an important sorting motif that is required for efficient targeting the protein to the plasma membrane |
| GO:0006520 amino acid metabolic process | NAS PMID:9537412 A novel gene encoding an integral membrane protein is mutate... | MODIFY | Summary: Amino acid metabolic process is too general; cystinosin transports rather than metabolises cystine. Reason: The specific process is lysosomal L-cystine export. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:9537412 CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0006749 glutathione metabolic process | IMP PMID:15956064 Altered status of glutathione and its metabolites in cystino... | MARK AS OVER ANNOTATED | Summary: Altered glutathione redox status in cystinotic cells is a downstream consequence of cystine storage. Reason: The study measures GSH/GSSG in patient cells; cystinosin does not perform any step of glutathione metabolism. Supporting Evidence: PMID:15956064 Although no reduction of total intracellular GSH content was found in cystinotic cells, it inversely correlated with cystine levels. |
| GO:0007420 brain development | IMP PMID:17471495 Non-verbal deficits in young children with a genetic metabol... | MARK AS OVER ANNOTATED | Summary: Based on psychometric testing of children with cystinosis. Reason: Non-verbal cognitive deficits in patients do not show that cystinosin participates in brain development; the inference is indirect. Supporting Evidence: PMID:17471495 the cystinosis group performed significantly more poorly than controls on the performance and processing speed subtests |
| GO:0015184 L-cystine transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IDA PMID:11689434 Cystinosin, the protein defective in cystinosis, is a H(+)-d... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IDA PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IDA PMID:22232659 Mechanism of proton/substrate coupling in the heptahelical l... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IDA PMID:36113465 Structure and mechanism of human cystine exporter cystinosin... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | IMP PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | NAS PMID:9537412 A novel gene encoding an integral membrane protein is mutate... | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015184 L-cystine transmembrane transporter activity | TAS Reactome:R-HSA-5340130 | ACCEPT | Summary: L-cystine transmembrane transporter activity is the core molecular function of cystinosin. Reason: Directly demonstrated by uptake assays with plasma-membrane-redirected cystinosin, electrophysiology and structures; patient lysosomes lack the activity and disease mutations abolish it. Supporting Evidence: PMID:11689434 COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:36113465 we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol |
| GO:0015295 solute:proton symporter activity | IDA PMID:11689434 Cystinosin, the protein defective in cystinosis, is a H(+)-d... | ACCEPT | Summary: Cystinosin is a cystine/H+ symporter. Reason: Transport depends on the transmembrane pH gradient and cystine binding is coupled to protonation, establishing proton symport. Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:22232659 we show that cystine binding is coupled to protonation of a clinically relevant aspartate buried in the membrane |
| GO:0015295 solute:proton symporter activity | IDA PMID:22232659 Mechanism of proton/substrate coupling in the heptahelical l... | ACCEPT | Summary: Cystinosin is a cystine/H+ symporter. Reason: Transport depends on the transmembrane pH gradient and cystine binding is coupled to protonation, establishing proton symport. Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:22232659 we show that cystine binding is coupled to protonation of a clinically relevant aspartate buried in the membrane |
| GO:0015295 solute:proton symporter activity | IDA PMID:36113465 Structure and mechanism of human cystine exporter cystinosin... | ACCEPT | Summary: Cystinosin is a cystine/H+ symporter. Reason: Transport depends on the transmembrane pH gradient and cystine binding is coupled to protonation, establishing proton symport. Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:22232659 we show that cystine binding is coupled to protonation of a clinically relevant aspartate buried in the membrane |
| GO:0015811 L-cystine transport | IDA PMID:11689434 Cystinosin, the protein defective in cystinosis, is a H(+)-d... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0015811 L-cystine transport | IDA PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0015811 L-cystine transport | IDA PMID:22232659 Mechanism of proton/substrate coupling in the heptahelical l... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0015811 L-cystine transport | IMP PMID:15128704 Molecular pathogenesis of cystinosis: effect of CTNS mutatio... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0015811 L-cystine transport | IMP PMID:7112129 Cystine transport is defective in isolated leukocyte lysosom... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0015811 L-cystine transport | NAS PMID:9537412 A novel gene encoding an integral membrane protein is mutate... | ACCEPT | Summary: Cystinosin mediates L-cystine transport out of lysosomes. Reason: Defective lysosomal cystine efflux is the cellular hallmark of CTNS deficiency and cystinosin carries the transport activity. Supporting Evidence: PMID:7112129 The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:15128704 infantile cystinosis generally resulting from a total loss of activity |
| GO:0033162 melanosome membrane | EXP PMID:22649030 Cystinosin is a melanosomal protein that regulates melanin s... | KEEP AS NON CORE | Summary: Cystinosin is present in melanosome membranes. Reason: Melanosomes are lysosome-related organelles; localisation is experimentally supported but secondary to the lysosomal role. Supporting Evidence: PMID:22649030 In vitro studies showed that cystinosin was located at melanosomes. |
| GO:0033162 melanosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cystinosin is present in melanosome membranes. Reason: Melanosomes are lysosome-related organelles; localisation is experimentally supported but secondary to the lysosomal role. Supporting Evidence: PMID:22649030 In vitro studies showed that cystinosin was located at melanosomes. |
| GO:0034486 vacuolar transmembrane transport | IBA GO_REF:0000033 | MODIFY | Summary: Vacuolar transmembrane transport is correct in kind; a precise term exists for cystinosin's process. Reason: GO:1904919 describes exactly cystine export from the lysosomal lumen to the cytosol. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:22232659 In humans, cystinosin exports the proteolysis-derived dimeric amino acid cystine from lysosomes and is impaired in cystinosis. |
| GO:0034486 vacuolar transmembrane transport | IDA PMID:11689434 Cystinosin, the protein defective in cystinosis, is a H(+)-d... | MODIFY | Summary: Vacuolar transmembrane transport is correct in kind; a precise term exists for cystinosin's process. Reason: GO:1904919 describes exactly cystine export from the lysosomal lumen to the cytosol. Proposed replacements: L-cystine transmembrane transport from lysosomal lumen to cytosol Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes PMID:22232659 In humans, cystinosin exports the proteolysis-derived dimeric amino acid cystine from lysosomes and is impaired in cystinosis. |
| GO:0035672 oligopeptide transmembrane transport | TAS Reactome:R-HSA-9959399 | REMOVE | Summary: Cystine is a disulfide-linked amino acid dimer, not an oligopeptide. Reason: The annotation derives from grouping CTNS under a Reactome 'SLC-mediated transport of oligopeptides' collection; cystinosin's substrate is L-cystine and it is not an oligopeptide transporter. Supporting Evidence: PMID:22232659 In humans, cystinosin exports the proteolysis-derived dimeric amino acid cystine from lysosomes and is impaired in cystinosis. Reactome:R-HSA-5340130 Cystinosin (CTNS) is an integral lysosomal membrane protein which can transport L-cystine (CySS-, the oxidative product of two cysteine molecules linked via a disulfide bond) together with H+ out of lysosomes. |
| GO:0042470 melanosome | IDA PMID:22649030 Cystinosin is a melanosomal protein that regulates melanin s... | KEEP AS NON CORE | Summary: Cystinosin is present in melanosomes. Reason: Experimentally supported localisation to a lysosome-related organelle; secondary to the lysosomal role. Supporting Evidence: PMID:22649030 In vitro studies showed that cystinosin was located at melanosomes. |
| GO:0046034 ATP metabolic process | IMP PMID:16439594 Decreased intracellular ATP content and intact mitochondrial... | MARK AS OVER ANNOTATED | Summary: Reduced ATP content in patient fibroblasts is a downstream effect of cystine storage. Reason: The same study found mitochondrial energy-generating capacity intact; cystinosin does not participate in ATP metabolism. Supporting Evidence: PMID:16439594 Patient's fibroblasts accumulated marked amounts of cystine and displayed a significant decrease in intracellular ATP content. |
| GO:0048021 regulation of melanin biosynthetic process | IMP PMID:22649030 Cystinosin is a melanosomal protein that regulates melanin s... | KEEP AS NON CORE | Summary: CTNS silencing reduces melanin synthesis via tyrosinase degradation. Reason: Experimentally supported role in pigmentation, likely secondary to its melanosomal/lysosomal transport function. Supporting Evidence: PMID:22649030 CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | REMOVE | Summary: Animal organ development is an uninformative electronic inference. Reason: Organ damage in cystinosis results from cystine storage; cystinosin does not participate in organ development. Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0048731 system development | IEA GO_REF:0000117 | REMOVE | Summary: System development is an uninformative electronic inference. Reason: Not supported by evidence of a developmental role for cystinosin. Supporting Evidence: PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0050890 cognition | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Electronic (ARBA) cognition annotation, repeating the phenotype-level association also carried by an IMP row. Reason: The same term is marked as an over-annotation on the mutant-phenotype row, and the claim is the same here. Cognitive impairment in cystinosis is a real consequence of losing cystinosin, but it arises from lysosomal cystine storage in the nervous system; cystinosin is a lysosomal cystine exporter and does not take part in cognition. The machine-generated row repeats the phenotype-level association and is treated the same way rather than removed. Supporting Evidence: PMID:17471495 the cystinosis group performed significantly more poorly than controls on the performance and processing speed subtests PMID:11689434 We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes |
| GO:0050890 cognition | IMP PMID:17471495 Non-verbal deficits in young children with a genetic metabol... | MARK AS OVER ANNOTATED | Summary: Based on psychometric testing of children with cystinosis. Reason: A patient cognitive profile is not evidence that cystinosin participates in cognition. Supporting Evidence: PMID:17471495 the cystinosis group performed significantly more poorly than controls on the performance and processing speed subtests |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-5223345 | KEEP AS NON CORE | Summary: Transmembrane transport is a correct but very general parent of cystinosin's function. Reason: Accurate; the specific L-cystine transport terms capture the core function. Supporting Evidence: Reactome:R-HSA-5340130 Cystinosin (CTNS) is an integral lysosomal membrane protein which can transport L-cystine (CySS-, the oxidative product of two cysteine molecules linked via a disulfide bond) together with H+ out of lysosomes. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detection in an exosome proteome is a high-throughput observation. Reason: Not a site of cystinosin function. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Protons are co-transported with cystine. Reason: Proton movement is the coupling ion of the symport mechanism rather than a separate process. Supporting Evidence: PMID:22232659 we show that cystine binding is coupled to protonation of a clinically relevant aspartate buried in the membrane |
| GO:1903432 regulation of TORC1 signaling | IDA PMID:36113465 Structure and mechanism of human cystine exporter cystinosin... | KEEP AS NON CORE | Summary: Cystinosin engages Ragulator-Rag in a conformation-dependent manner, linking it to TORC1 signalling. Reason: Supported structurally and functionally, but secondary to the core cystine export role. Supporting Evidence: PMID:36113465 show conformation-dependent Ragulator-Rag complex engagement |
| GO:1903432 regulation of TORC1 signaling | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cystinosin engages Ragulator-Rag in a conformation-dependent manner, linking it to TORC1 signalling. Reason: Supported structurally and functionally, but secondary to the core cystine export role. Supporting Evidence: PMID:36113465 show conformation-dependent Ragulator-Rag complex engagement |
| GO:1904263 positive regulation of TORC1 signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based positive regulation of TORC1 signalling. Reason: Consistent with Ragulator-Rag engagement; direction and physiological significance in human cells are less established, so non-core. Supporting Evidence: PMID:36113465 show conformation-dependent Ragulator-Rag complex engagement |
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Download this section (compressed HTML)Q: Is cystinosin's Ragulator-Rag engagement a transporter-independent signalling function, and does it contribute to cystinosis pathology independent of cystine storage?
Suggested experts: lysosomal transporter biologists, mTORC1 signalling experts
Experiment: Express transport-dead but Ragulator-binding cystinosin mutants in CTNS-null proximal tubule cells and measure mTORC1 activity and cystine levels.
Hypothesis: mTORC1 dysregulation in cystinosis is partly independent of cystine accumulation.
Type: genetic complementation
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