Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:11417227 Identification and characterisation of human xCT that co-exp...	ACCEPT	Summary: This is the primary molecular function of SLC7A11. PMID:11417227 (Bassi et al., 2001) directly demonstrated that human xCT co-expressed with 4F2hc mediates Na+-independent cystine/glutamate antiport with Km values of 43 uM for cystine and 92 uM for glutamate. Reason: Core molecular function established by direct transport assays in reconstituted systems. Multiple studies confirm this antiporter activity with defined kinetics. Supporting Evidence: PMID:11417227 The amino acid transport activity induced by the co-expression of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific for L-cystine, L-glutamate and L-aspartate file:human/SLC7A11/SLC7A11-deep-research-falcon.md System xc− exchanges extracellular L-cystine for intracellular L-glutamate at approximately 1:1 stoichiometry, enabling cystine import that is reduced intracellularly to cysteine for glutathione (GSH) synthesis; reported Km values are ~50 µM (cystine) and ~200 µM (glutamate)
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:15151999 Membrane topology of system xc- light subunit reveals a re-e...	ACCEPT	Summary: PMID:15151999 (Gasol et al., 2004) characterized membrane topology and transport function, reporting Km of 110 uM for cystine and 224 uM for glutamate. Reason: Confirms core antiporter activity with detailed kinetic characterization and membrane topology analysis. Supporting Evidence: PMID:15151999 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine and L-glutamate (system x(c)(-))
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:34120018 N-acetylcysteine, xCT and suppression of Maxi-chloride chann...	ACCEPT	Summary: PMID:34120018 (Lofthouse et al., 2021) demonstrated xCT-mediated cystine/glutamate antiport in human placenta, including N-acetylcysteine transport. Reason: Confirms antiporter activity in physiologically relevant tissue context (placenta). Supporting Evidence: PMID:34120018 Maternoplacental N-acetylcysteine administration stimulated intracellular glutamate efflux suggesting a role of the exchange transporter xCT
GO:0015327 cystine:glutamate antiporter activity	RCA PMID:34880232 Molecular basis for redox control by the human cystine/gluta...	ACCEPT	Summary: PMID:34880232 (Parker et al., 2021) provided cryo-EM structure of xCT-4F2hc complex with L-glutamate bound, revealing molecular basis of antiporter function. Reason: Structural evidence confirming antiporter mechanism with substrate-bound structure. Supporting Evidence: PMID:34880232 Here we present the cryo-EM structure of system xc- in both the apo and glutamate bound states
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:35352032 The structure of erastin-bound xCT-4F2hc complex reveals mol...	ACCEPT	Summary: PMID:35352032 (Yan et al., 2022) provided erastin-bound xCT-4F2hc structure showing inhibitor binding site and transport mechanism. Reason: Structural and functional evidence for antiporter activity with inhibitor binding site. Supporting Evidence: PMID:35352032 The small-molecule compound erastin induces ferroptosis via inhibiting the cystine-glutamate antiporter system xc–
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:35245456 Kynurenine importation by SLC7A11 propagates anti-ferroptoti...	ACCEPT	Summary: PMID:35245456 (Fiore et al., 2022) confirmed cystine:glutamate antiport while also discovering kynurenine transport capability. Reason: Confirms core antiporter function in context of expanded substrate repertoire study. Supporting Evidence: PMID:35245456 We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression
GO:0015327 cystine:glutamate antiporter activity	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 confirmed canonical cystine:glutamate antiporter function while discovering novel lysosomal proton channel activity. Reason: Confirms core antiporter function in context of study expanding known functions. Supporting Evidence: PMID:40280132 SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate
GO:0015327 cystine:glutamate antiporter activity	TAS PMID:10206947 Cloning and expression of a plasma membrane cystine/glutamat...	ACCEPT	Summary: PMID:10206947 (Sato et al., 1999) was the original cloning paper identifying xCT as the light chain of system xc-. Reason: Foundational paper establishing identity and function of xCT. Supporting Evidence: PMID:10206947 The latter protein, named xCT, showed a significant homology with those recently reported to mediate cationic or zwitterionic amino acid transport when co-expressed with 4F2hc
GO:0015811 L-cystine transport	IEA GO_REF:0000120	ACCEPT	Summary: Automated annotation based on ARBA rules and orthology. L-cystine transport is the primary biological process mediated by SLC7A11. Reason: Core biological process - IEA is redundant with multiple IDA annotations but correctly captures the function.
GO:0015811 L-cystine transport	IDA PMID:11417227 Identification and characterisation of human xCT that co-exp...	ACCEPT	Summary: Direct demonstration of L-cystine uptake via xCT/4F2hc complex with Km = 43 uM. Reason: Core biological process with direct kinetic evidence. Supporting Evidence: PMID:11417227 The amino acid transport activity induced by the co-expression of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific for L-cystine, L-glutamate and L-aspartate
GO:0015811 L-cystine transport	IDA PMID:15151999 Membrane topology of system xc- light subunit reveals a re-e...	ACCEPT	Summary: Confirmed cystine transport with Km = 110 uM in detailed topology study. Reason: Core biological process confirmed with kinetic parameters. Supporting Evidence: PMID:15151999 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine and L-glutamate (system x(c)(-))
GO:0015811 L-cystine transport	IDA PMID:34880232 Molecular basis for redox control by the human cystine/gluta...	ACCEPT	Summary: Structural study confirming cystine transport mechanism. Reason: Core biological process supported by structural evidence. Supporting Evidence: PMID:34880232 Under redox stress conditions mammalian cells use a specific system to increase cystine uptake to increase GSH synthesis, termed system xc− a dedicated cystine-glutamate antiporter
GO:0015811 L-cystine transport	IDA PMID:35352032 The structure of erastin-bound xCT-4F2hc complex reveals mol...	ACCEPT	Summary: Confirmed cystine transport in context of erastin inhibition study. Reason: Core biological process with inhibitor sensitivity data. Supporting Evidence: PMID:35352032 inhibiting xCT impairs cystine uptake, causing an accumulation of ROS and suppressing tumor growth
GO:0015811 L-cystine transport	IDA PMID:11133847 Structure, function, and regulation of human cystine/glutama...	ACCEPT	Summary: PMID:11133847 (Bridges et al., 2001) characterized xCT function in retinal pigment epithelial cells. Reason: Core biological process demonstrated in RPE cells. Supporting Evidence: PMID:11133847 Coexpression of human xCT with 4F2hc in HeLa cells leads to the induction of cystine and glutamate uptake with characteristics similar to that of x(c)(-)
GO:0015811 L-cystine transport	IDA PMID:11213471 Molecular cloning and expression of human xCT, the light cha...	ACCEPT	Summary: PMID:11213471 (Sato et al., 2000) original molecular cloning paper confirming cystine transport function. Reason: Foundational paper establishing cystine transport function. Supporting Evidence: PMID:11213471 Transport of system xc- is an exchange agency with high specificity for anionic form of cystine and glutamate
GO:0015813 L-glutamate transmembrane transport	IEA GO_REF:0000117	ACCEPT	Summary: ARBA annotation capturing glutamate export function of the antiporter. Reason: Core biological process - glutamate efflux is integral to antiporter mechanism.
GO:0015813 L-glutamate transmembrane transport	IDA PMID:11417227 Identification and characterisation of human xCT that co-exp...	ACCEPT	Summary: Direct demonstration of glutamate efflux coupled to cystine import with Km = 92 uM. Reason: Core biological process with kinetic evidence. Supporting Evidence: PMID:11417227 This activity also functioned in an exchange mode (e.g. cystine/glutamate) with a substrate stoichiometry of 1:1
GO:0015813 L-glutamate transmembrane transport	IDA PMID:15151999 Membrane topology of system xc- light subunit reveals a re-e...	ACCEPT	Summary: Glutamate transport confirmed with Km = 224 uM. Reason: Core biological process with kinetic parameters. Supporting Evidence: PMID:15151999 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine and L-glutamate (system x(c)(-))
GO:0015813 L-glutamate transmembrane transport	IDA PMID:34880232 Molecular basis for redox control by the human cystine/gluta...	ACCEPT	Summary: Structural study with glutamate-bound structure. Reason: Core biological process with structural evidence of glutamate binding. Supporting Evidence: PMID:34880232 Here we present the cryo-EM structure of system xc- in both the apo and glutamate bound states
GO:0015813 L-glutamate transmembrane transport	IDA PMID:35352032 The structure of erastin-bound xCT-4F2hc complex reveals mol...	ACCEPT	Summary: Glutamate transport in context of erastin inhibition. Reason: Core biological process confirmed. Supporting Evidence: PMID:35352032 The small-molecule compound erastin induces ferroptosis via inhibiting the cystine-glutamate antiporter system xc–
GO:0015813 L-glutamate transmembrane transport	IDA PMID:11133847 Structure, function, and regulation of human cystine/glutama...	ACCEPT	Summary: Glutamate transport in RPE cells. Reason: Core biological process in physiological context. Supporting Evidence: PMID:11133847 the uptake of glutamate in the absence of Na(+) occurs exclusively via x(c)(-)
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Automated annotation for plasma membrane localization. Reason: Core localization - xCT functions primarily at the plasma membrane.
GO:0005886 plasma membrane	IDA PMID:11417227 Identification and characterisation of human xCT that co-exp...	ACCEPT	Summary: Direct demonstration of plasma membrane localization. Reason: Core localization established by immunofluorescence and functional studies. Supporting Evidence: PMID:11417227 The amino acid transport activity induced by the co-expression of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific for L-cystine, L-glutamate and L-aspartate
GO:0005886 plasma membrane	IDA PMID:15151999 Membrane topology of system xc- light subunit reveals a re-e...	ACCEPT	Summary: Membrane topology study confirming plasma membrane localization. Reason: Core localization with detailed topology mapping. Supporting Evidence: PMID:15151999 we propose a topological model for xCT of 12 transmembrane domains with the N and C termini located inside the cell
GO:0005886 plasma membrane	IDA PMID:40246981 Galectin-13 reduces membrane localization of SLC7A11 for fer...	ACCEPT	Summary: PMID:40246981 studied galectin-13-mediated regulation of SLC7A11 membrane localization. Reason: Confirms plasma membrane as functional location. Supporting Evidence: PMID:40246981 Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation
GO:0005886 plasma membrane	IPI PMID:34880232 Molecular basis for redox control by the human cystine/gluta...	ACCEPT	Summary: Co-localization with SLC3A2 at plasma membrane in structural study. Reason: Core localization confirmed through complex formation. Supporting Evidence: PMID:34880232 The light subunit of human xc- transporter, xCT, (SLC7A11), consists of 12 transmembrane helices (TMs)
GO:0005886 plasma membrane	TAS Reactome:R-HSA-375131	ACCEPT	Summary: Reactome pathway annotation for basigin interactions at plasma membrane. Reason: Core localization supported by pathway database.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-378513	ACCEPT	Summary: Reactome pathway for SLC7A11-mediated cystine/glutamate exchange. Reason: Core localization in transport pathway context.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9761841	ACCEPT	Summary: Reactome NFE2L2-dependent SLC7A11 expression pathway. Reason: Core localization in regulatory pathway context.
GO:0110076 negative regulation of ferroptosis	IDA PMID:40246981 Galectin-13 reduces membrane localization of SLC7A11 for fer...	ACCEPT	Summary: PMID:40246981 demonstrated that SLC7A11 suppresses ferroptosis; galectin-13 reduces membrane SLC7A11 to propagate ferroptosis. Reason: Core function - SLC7A11 is a central suppressor of ferroptosis through cystine import and GSH/GPX4 pathway. This is one of the most well-established physiological consequences of xCT function. Supporting Evidence: PMID:40246981 Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation
GO:0110076 negative regulation of ferroptosis	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 confirmed anti-ferroptotic function while discovering lysosomal role. Reason: Core function confirmed in context of expanded functional characterization. Supporting Evidence: PMID:40280132 SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis
GO:0110076 negative regulation of ferroptosis	IDA PMID:35245456 Kynurenine importation by SLC7A11 propagates anti-ferroptoti...	ACCEPT	Summary: PMID:35245456 showed kynurenine import via SLC7A11 propagates anti-ferroptotic signaling. Reason: Core function demonstrated through novel kynurenine pathway. Supporting Evidence: PMID:35245456 We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular location annotation based on lysosomal membrane localization. Reason: Recently validated secondary localization - IDA evidence in PMID:40280132 confirms lysosomal membrane localization.
GO:0005765 lysosomal membrane	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 directly demonstrated SLC7A11 localization and function at lysosomal membranes where it acts as a proton channel. Reason: Novel secondary localization with direct experimental evidence for functional role at lysosomes. Supporting Evidence: PMID:40280132 SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate
GO:0015252 proton channel activity	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 discovered that SLC7A11 functions as an unconventional proton channel at lysosomal membranes, independent of its antiporter activity. Reason: Novel molecular function with direct experimental evidence. This represents a newly discovered activity distinct from the canonical antiporter function. Supporting Evidence: PMID:40280132 SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate
GO:0022840 leak channel activity	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 characterized SLC7A11 as having leak channel properties for protons at lysosomal membranes. Reason: Novel molecular function - proton leak channel activity at lysosomes. Supporting Evidence: PMID:40280132 SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate
GO:0022840 leak channel activity	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: Duplicate annotation in GOA - same evidence as above. Reason: Same evidence supports leak channel activity at lysosomes. Supporting Evidence: PMID:40280132 SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis
GO:0035752 lysosomal lumen pH elevation	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from mouse ortholog. Reason: Supported by direct experimental evidence in PMID:40280132 demonstrating lysosomal pH elevation via proton channel activity.
GO:0035752 lysosomal lumen pH elevation	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 demonstrated that SLC7A11 proton channel activity elevates lysosomal lumen pH. Reason: Novel biological process with direct experimental evidence. Supporting Evidence: PMID:40280132 SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis
GO:1902600 proton transmembrane transport	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: PMID:40280132 demonstrated proton transport activity at lysosomal membranes. Reason: Novel biological process supporting proton channel function discovery. Supporting Evidence: PMID:40280132 SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate
GO:1902600 proton transmembrane transport	IDA PMID:40280132 SLC7A11 is an unconventional H(+) transporter in lysosomes.	ACCEPT	Summary: Duplicate annotation in GOA - same evidence as above. Reason: Same evidence supports proton transmembrane transport. Supporting Evidence: PMID:40280132 SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis
GO:0140924 L-kynurenine transmembrane transport	IDA PMID:35245456 Kynurenine importation by SLC7A11 propagates anti-ferroptoti...	ACCEPT	Summary: PMID:35245456 (Fiore et al., 2022) discovered that SLC7A11 imports L-kynurenine, a tryptophan metabolite, which propagates anti-ferroptotic signaling. Reason: Novel expanded substrate specificity with direct experimental evidence. Kynurenine import contributes to anti-ferroptotic function. Supporting Evidence: PMID:35245456 We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression
GO:0140926 L-kynurenine transmembrane transporter activity	IDA PMID:35245456 Kynurenine importation by SLC7A11 propagates anti-ferroptoti...	ACCEPT	Summary: PMID:35245456 demonstrated L-kynurenine transporter activity for SLC7A11. Reason: Novel molecular function - expanded substrate specificity beyond cystine/glutamate. Supporting Evidence: PMID:35245456 We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression
GO:0003333 amino acid transmembrane transport	IBA GO_REF:0000033	MODIFY	Summary: IBA annotation from phylogenetic inference. While technically correct, this term is too general for a transporter with well-characterized substrate specificity. Reason: Too general. SLC7A11 specifically transports L-cystine and L-glutamate as an antiporter, plus recently discovered L-kynurenine. The more specific terms GO:0015811 (L-cystine transport) and GO:0015813 (L-glutamate transmembrane transport) are more appropriate. Proposed replacements: L-cystine transport L-glutamate transmembrane transport
GO:0015179 L-amino acid transmembrane transporter activity	IBA GO_REF:0000033	MODIFY	Summary: IBA annotation from phylogenetic inference. Too general for a transporter with well-characterized antiporter mechanism. Reason: Too general. SLC7A11 has cystine:glutamate antiporter activity (GO:0015327), which is the appropriate specific term. Proposed replacements: cystine:glutamate antiporter activity
GO:0006865 amino acid transport	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: IEA from InterPro domain. Too general for well-characterized transporter. Reason: Too general. The specific transport processes (L-cystine, L-glutamate) are better captured by more specific annotations already present.
GO:0022857 transmembrane transporter activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA from InterPro annotation. Too general for well-characterized antiporter. Reason: Too general. GO:0015327 (cystine:glutamate antiporter activity) is the appropriate specific molecular function.
GO:0055085 transmembrane transport	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA from InterPro. Very general biological process. Reason: Too general. Specific transport processes are well-annotated.
GO:0016020 membrane	IEA GO_REF:0000120	MODIFY	Summary: IEA annotation - too general for well-characterized membrane protein. Reason: Too general. SLC7A11 is specifically localized to plasma membrane (primary) and lysosomal membrane (secondary), both of which are already annotated. Proposed replacements: plasma membrane
GO:0016020 membrane	TAS PMID:10206947 Cloning and expression of a plasma membrane cystine/glutamat...	MODIFY	Summary: TAS annotation from original cloning paper. Too general. Reason: Too general. Original paper demonstrated plasma membrane localization. Proposed replacements: plasma membrane Supporting Evidence: PMID:10206947 The latter protein, named xCT, showed a significant homology with those recently reported to mediate cationic or zwitterionic amino acid transport when co-expressed with 4F2hc
GO:0089718 amino acid import across plasma membrane	IDA PMID:11417227 Identification and characterisation of human xCT that co-exp...	MODIFY	Summary: IDA from functional characterization study. While correct, this is less specific than the available terms. Reason: Partially accurate but less specific. SLC7A11 imports L-cystine (not general amino acids) in exchange for glutamate export. GO:0015811 (L-cystine transport) is more specific and accurate. Proposed replacements: L-cystine transport Supporting Evidence: PMID:11417227 The amino acid transport activity induced by the co-expression of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific for L-cystine, L-glutamate and L-aspartate
GO:0043067 regulation of programmed cell death	IEA GO_REF:0000117	MODIFY	Summary: ARBA annotation linking xCT to cell death regulation. Too vague. Reason: Too general. SLC7A11 specifically negatively regulates ferroptosis (GO:0110076), a specific form of regulated cell death, through its role in GSH synthesis. Proposed replacements: negative regulation of ferroptosis
GO:0005515 protein binding	IPI PMID:21397861 CD44 variant regulates redox status in cancer cells by stabi...	REMOVE	Summary: PMID:21397861 (Ishimoto et al., 2011) showed CD44 variant interaction stabilizes xCT to regulate redox status in cancer cells. Reason: "Protein binding" is uninformative per GO curation guidelines. The specific interaction with CD44 variant (CD44v) that stabilizes xCT would be better captured by a more specific term if available. Supporting Evidence: PMID:21397861 CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH)
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	REMOVE	Summary: High-throughput protein interaction study. Reason: "Protein binding" is uninformative. HT-PPI studies often capture non-specific or context-dependent interactions. Supporting Evidence: PMID:27173435 Here we use affinity proteomics, genetics and cell biology to interrogate cilia
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Binary protein interactome mapping study. Detected interactions with SLC3A2-4 isoform and keratin-associated proteins. Reason: "Protein binding" is uninformative. The SLC3A2 interaction is essential for function and better captured by complex formation annotations; keratin interactions may be non-specific. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Binary protein interactome mapping study - additional interaction. Reason: "Protein binding" is uninformative per GO guidelines. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Binary protein interactome mapping study - third interaction. Reason: "Protein binding" is uninformative per GO guidelines. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0005515 protein binding	IPI PMID:34880232 Molecular basis for redox control by the human cystine/gluta...	REMOVE	Summary: Structural study showing xCT-SLC3A2 complex. The interaction with SLC3A2 is essential for function. Reason: "Protein binding" is uninformative. The xCT-SLC3A2 heterodimer formation is a functional requirement, not just protein binding. This is better represented by the complex formation in ComplexPortal (CPX-8190). Supporting Evidence: PMID:34880232 Here we present the cryo-EM structure of system xc- in both the apo and glutamate bound states
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Multimodal cell maps study - high-throughput protein interaction data. Reason: "Protein binding" is uninformative per GO guidelines. Supporting Evidence: PMID:40205054 Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins
GO:0005515 protein binding	IPI PMID:40355756 The solute carrier superfamily interactome.	REMOVE	Summary: Solute carrier superfamily interactome study detecting SLC7A11-SLC3A2 interaction. Reason: "Protein binding" is uninformative. The SLC3A2 interaction is essential for heterodimer function and better captured by functional annotations. Supporting Evidence: PMID:40355756 Here, we used a systematic AP-MS approach to determine the protein interaction network of human solute carriers
GO:0009986 cell surface	IDA PMID:25063885 KSHV attachment and entry are dependent on αVβ3 integrin loc...	ACCEPT	Summary: PMID:25063885 detected SLC7A11 at cell surface in context of KSHV entry study. Reason: Acceptable localization annotation - cell surface is parent of plasma membrane and represents the functionally relevant location for the transporter. Supporting Evidence: PMID:25063885 the presence of CD98 and heparan sulfate (HS), the putative attachment receptor, was more variable
GO:0031528 microvillus membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location annotation based on placental syncytiotrophoblast microvillus membrane localization. Reason: Cell type-specific localization in placenta. This is a specialized localization, not universally applicable. Supporting Evidence: PMID:34120018 xCT, which was localised to the microvillous membrane of the placental syncytiotrophoblast
GO:0031526 brush border membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse ortholog - intestinal/renal brush border. Reason: Cell type-specific localization in polarized epithelia. Not the primary localization but relevant in specific tissue contexts.
GO:0045177 apical part of cell	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse ortholog. Reason: Cell type-specific localization in polarized cells. Consistent with brush border and microvillus membrane annotations.
GO:0097449 astrocyte projection	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer - astrocyte-specific localization. Reason: Cell type-specific localization in astrocytes. xCT is highly expressed in brain and plays important role in astrocyte glutamate release, but this is not the universal localization.
GO:0009636 response to toxic substance	IDA PMID:17575980 Differential expression of intestinal membrane transporters ...	KEEP AS NON CORE	Summary: PMID:17575980 examined differential expression of intestinal transporters in cholera patients, showing xCT involvement in response. Reason: Context-specific response - xCT expression changes in response to toxic insults/disease states as part of oxidative stress response, but this is not the core function. Supporting Evidence: PMID:17575980 Two amino acid transporters, SLC7A11 and SLC6A14, were upregulated in acute cholera patients compared to convalescence

Core Functions

Primary molecular function established by multiple structural and functional studies. SLC7A11 (xCT) forms a disulfide-linked heterodimer with SLC3A2 (4F2hc) to mediate Na+-independent, electroneutral 1:1 exchange of extracellular L-cystine for intracellular L-glutamate. Km values: cystine ~43-110 uM, glutamate ~48-224 uM.

Molecular Function:

cystine:glutamate antiporter activity

Directly Involved In:

L-cystine transport L-glutamate transmembrane transport

Cellular Locations:

plasma membrane

Core physiological function - by providing cysteine for GSH synthesis, xCT enables GPX4 to detoxify lipid peroxides and suppress ferroptosis.

Molecular Function:

cystine:glutamate antiporter activity

Directly Involved In:

negative regulation of ferroptosis

Cellular Locations:

plasma membrane

Novel function discovered in PMID:40280132 - SLC7A11 acts as an unconventional proton channel at lysosomal membranes, contributing to lysosomal pH regulation.

Molecular Function:

proton channel activity

Directly Involved In:

lysosomal lumen pH elevation proton transmembrane transport

Cellular Locations:

lysosomal membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10206947

Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins.

Original cloning identified xCT as the light chain forming heterodimer with 4F2hc for system xc- activity

"The latter protein, named xCT, showed a significant homology with those recently reported to mediate cationic or zwitterionic amino acid transport when co-expressed with 4F2hc"

PMID:11133847

Structure, function, and regulation of human cystine/glutamate transporter in retinal pigment epithelial cells.

PMID:11213471

Molecular cloning and expression of human xCT, the light chain of amino acid transport system xc-.

PMID:11417227

Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-.

Demonstrated Na+-independent transport activity specific for L-cystine, L-glutamate and L-aspartate

"The amino acid transport activity induced by the co-expression of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific for L-cystine, L-glutamate and L-aspartate"
Established 1:1 stoichiometry of cystine/glutamate exchange

"This activity also functioned in an exchange mode (e.g. cystine/glutamate) with a substrate stoichiometry of 1:1"

PMID:15151999

Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility.

Established 12-TM topology with intracellular N and C termini

"we propose a topological model for xCT of 12 transmembrane domains with the N and C termini located inside the cell"
Identified re-entrant loop with substrate-restricted accessibility

"Studies of biotinylation and accessibility to sulfhydryl reagents revealed a re-entrant loop within intracellular loops 2 and 3"

PMID:17575980

Differential expression of intestinal membrane transporters in cholera patients.

SLC7A11 upregulated in acute cholera patients as part of response to toxic substance

"Two amino acid transporters, SLC7A11 and SLC6A14, were upregulated in acute cholera patients compared to convalescence"

PMID:21397861

CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth.

CD44 variant interacts with xCT and controls intracellular GSH levels

"CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH)"
Ablation of CD44 induces loss of xCT from cell surface

"Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer"

PMID:25063885

KSHV attachment and entry are dependent on αVβ3 integrin localized to specific cell surface microdomains and do not correlate with the presence of heparan sulfate.

CD98 detected at cell surface microdomains

"the presence of CD98 and heparan sulfate (HS), the putative attachment receptor, was more variable"

PMID:27173435

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:34120018

N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta.

xCT mediates N-acetylcysteine uptake in placenta

"This study suggests that xCT mediates N-acetylcysteine uptake into the placenta"
xCT localized to microvillous membrane of placental syncytiotrophoblast

"xCT, which was localised to the microvillous membrane of the placental syncytiotrophoblast"

PMID:34880232

Molecular basis for redox control by the human cystine/glutamate antiporter system xc().

Cryo-EM structure of system xc- in apo and glutamate bound states

"Here we present the cryo-EM structure of system xc- in both the apo and glutamate bound states"
xCT consists of 12 transmembrane helices adopting canonical APC superfamily fold

"The light subunit of human xc- transporter, xCT, (SLC7A11), consists of 12 transmembrane helices (TMs)"
System xc- is a dedicated cystine-glutamate antiporter

"Under redox stress conditions mammalian cells use a specific system to increase cystine uptake to increase GSH synthesis, termed system xc− a dedicated cystine-glutamate antiporter"

PMID:35245456

Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling.

SLC7A11 imports kynurenine which propagates anti-ferroptotic signaling

"We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression"

PMID:35352032

The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis.

Erastin induces ferroptosis by inhibiting system xc-

"The small-molecule compound erastin induces ferroptosis via inhibiting the cystine-glutamate antiporter system xc–"
xCT regulates ferroptosis in multiple pathophysiological processes

"Recent studies have shown that xCT (SLC7A11) regulates ferroptosis in liver fibrosis, cardiomyopathy, and numerous other pathophysiological processes"

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:40246981

Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation.

Galectin-13 inhibits plasma membrane localization of SLC7A11 to promote ferroptosis

"Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation"

PMID:40280132

SLC7A11 is an unconventional H(+) transporter in lysosomes.

SLC7A11 mediates slow lysosomal H+ leak through cystine/glutamate flux

"SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate"
SLC7A11 deficiency causes lysosomal over-acidification and ferroptosis

"SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis"

PMID:40355756

The solute carrier superfamily interactome.

Reactome:R-HSA-375131

Basigin binds CD98 complex

Reactome:R-HSA-378513

SLC7A11-mediated exchange of extracellular cysteine and cytosolic glutamate

Reactome:R-HSA-9761841

AcK-NFE2L2-dependent SLC7A11 expression

file:human/SLC7A11/SLC7A11-deep-research-falcon.md

Deep research report on SLC7A11

System xc− exchanges extracellular L-cystine for intracellular L-glutamate at ~1:1 stoichiometry to supply cysteine for GSH synthesis

"System xc− exchanges extracellular L-cystine for intracellular L-glutamate at approximately 1:1 stoichiometry, enabling cystine import that is reduced intracellularly to cysteine for glutathione (GSH) synthesis; reported Km values are ~50 µM (cystine) and ~200 µM (glutamate)"

Suggested Experiments

Experiment: Comparative analysis of SLC7A11 proton channel vs antiporter activity under different cellular conditions (normal vs stress, plasma membrane vs lysosome) to understand the relative contributions of the two distinct activities.

Experiment: Structure-function studies to identify residues that separate proton channel from antiporter activity, which could enable selective modulation of one activity without affecting the other.

📚 Additional Documentation

Deep Research Falcon

(SLC7A11-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-27T12:30:44.075790'
end_time: '2025-12-27T12:35:13.257951'
duration_seconds: 269.18
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: SLC7A11
gene_symbol: SLC7A11
uniprot_accession: Q9UPY5
protein_description: 'RecName: Full=Cystine/glutamate transporter {ECO:0000305};
AltName: Full=Amino acid transport system xc-; AltName: Full=Calcium channel blocker
resistance protein CCBR1; AltName: Full=Solute carrier family 7 member 11; AltName:
Full=xCT {ECO:0000303|PubMed:11213471};'
gene_info: Name=SLC7A11 {ECO:0000312|HGNC:HGNC:11059};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the amino acid-polyamine-organocation (APC)
protein_domains: AA/rel_permease1. (IPR002293); AminoAcid_Transporter. (IPR050598);
L_AA_transporter. (IPR004760); AA_permease_2 (PF13520)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 16

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9UPY5
Protein Description: RecName: Full=Cystine/glutamate transporter {ECO:0000305}; AltName: Full=Amino acid transport system xc-; AltName: Full=Calcium channel blocker resistance protein CCBR1; AltName: Full=Solute carrier family 7 member 11; AltName: Full=xCT {ECO:0000303|PubMed:11213471};
Gene Information: Name=SLC7A11 {ECO:0000312|HGNC:HGNC:11059};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the amino acid-polyamine-organocation (APC)
Key Domains: AA/rel_permease1. (IPR002293); AminoAcid_Transporter. (IPR050598); L_AA_transporter. (IPR004760); AA_permease_2 (PF13520)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SLC7A11" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SLC7A11' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SLC7A11 (gene ID: SLC7A11, UniProt: Q9UPY5) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9UPY5
Protein Description: RecName: Full=Cystine/glutamate transporter {ECO:0000305}; AltName: Full=Amino acid transport system xc-; AltName: Full=Calcium channel blocker resistance protein CCBR1; AltName: Full=Solute carrier family 7 member 11; AltName: Full=xCT {ECO:0000303|PubMed:11213471};
Gene Information: Name=SLC7A11 {ECO:0000312|HGNC:HGNC:11059};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the amino acid-polyamine-organocation (APC)
Key Domains: AA/rel_permease1. (IPR002293); AminoAcid_Transporter. (IPR050598); L_AA_transporter. (IPR004760); AA_permease_2 (PF13520)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SLC7A11" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SLC7A11 (gene ID: SLC7A11, UniProt: Q9UPY5) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Human SLC7A11 (UniProt Q9UPY5; xCT)

Plan and verification
- Identity verification: The target gene symbol SLC7A11 corresponds to the human cystine/glutamate antiporter light chain xCT, the catalytic subunit of system xc−, encoded in Homo sapiens. It forms a disulfide-linked heterodimer with the heavy chain SLC3A2 (4F2hc), consistent with the amino acid–polyamine–organocation (APC) transporter family and 12-transmembrane architecture, aligning with UniProt-provided family/domain expectations (AA/rel_permease1; L-amino acid transporter) (jakobsen2024exploringaminoacid pages 12-14, jakobsen2024exploringaminoacid pages 28-30). This matches the mandated identity and organism checks; no conflicting gene symbol literature was encountered.

Key concepts and definitions (current understanding)
- Molecular identity and complex: SLC7A11 (xCT) is the light-chain catalytic subunit of system xc−, a heterodimeric amino acid transporter with SLC3A2 (4F2hc) as the glycosylated heavy chain; the subunits are covalently linked and co-traffic to the plasma membrane (jakobsen2024exploringaminoacid pages 12-14, zhang2024theroleof pages 1-2). System xc− is Na+-independent and located predominantly at the cell surface (jakobsen2024exploringaminoacid pages 12-14).
- Primary biochemical function: System xc− exchanges extracellular L-cystine for intracellular L-glutamate at approximately 1:1 stoichiometry, enabling cystine import that is reduced intracellularly to cysteine for glutathione (GSH) synthesis; reported Km values are ~50 µM (cystine) and ~200 µM (glutamate) (jakobsen2024exploringaminoacid pages 12-14). This transport is a central node for cellular redox control and antioxidant defense (jakobsen2024exploringaminoacid pages 12-14, li2024slc7a11inhepatocellular pages 1-2).
- Pathway roles: By supporting GSH synthesis, SLC7A11 limits lipid peroxidation and opposes ferroptosis, an iron-dependent form of regulated cell death; pharmacologic or genetic blockade of SLC7A11/system xc− induces ferroptosis (li2024slc7a11inhepatocellular pages 1-2, jakobsen2024exploringaminoacid pages 12-14). Disulfidptosis, a distinct metabolic cell death observed under glucose deprivation with high SLC7A11 activity, is mechanistically linked to disulfide stress, further connecting SLC7A11 to redox-driven cell fates (qiu2025slc7a11asa pages 1-3).

Recent developments and latest research (2023–2024 priority)
- Transporter pharmacology and oncology targeting: A 2024 review synthesizes inhibitor efforts against xCT (including erastin, sulfasalazine, sorafenib), emphasizes challenges in selectivity, and catalogs structure-guided discovery approaches; it also summarizes clinical context such as an early glioma trial of sulfasalazine that was terminated (jakobsen2024exploringaminoacid pages 30-31). Disease-focused 2024 reviews in HCC and ovarian cancer highlight SLC7A11 overexpression, therapy resistance, and the rationale for inducing ferroptosis via xCT inhibition (li2024slc7a11inhepatocellular pages 1-2, fantone2024roleofslc7a11xct pages 1-2).
- Structural insight: Recent transporter reviews reference cryo-EM structures of the human SLC7A11–SLC3A2 complex that informed substrate path and small-molecule engagement models; these structural advances are shaping inhibitor hypotheses (jakobsen2024exploringaminoacid pages 12-14, jakobsen2024exploringaminoacid pages 28-30).
- Trafficking and post-translational regulation: New 2024 data identify a critical role for the xCT C-terminal Lys473 in secretory pathway progression; K473 substitutions alter glycosylation status, cause ER/Golgi retention, and abrogate plasma-membrane activity, pointing to acetylation/deacetylation as regulatory checkpoints for trafficking (koppin2024lysine473regulates pages 1-2). Together with the established need for SLC3A2 as a chaperone, this clarifies assembly and membrane delivery mechanisms (koppin2024lysine473regulates pages 1-2, jakobsen2024exploringaminoacid pages 12-14).

Current applications and real-world implementations
- Oncology applications:
- Small-molecule inhibitors erastin and sulfasalazine are widely used to inhibit system xc− in preclinical models to induce ferroptosis; sorafenib is also discussed in the context of HCC and ferroptosis modulation (li2024slc7a11inhepatocellular pages 1-2, jakobsen2024exploringaminoacid pages 12-14, fantone2024roleofslc7a11xct pages 1-2).
- The clinical pathway has seen exploratory attempts such as sulfasalazine in glioma; while that trial was terminated, it established safety/feasibility considerations and informs ongoing translational efforts (jakobsen2024exploringaminoacid pages 30-31).
- Beyond oncology: 2024 translational reviews implicate SLC7A11 in diabetic wound healing via immune and oxidative-stress modulation, suggesting therapeutic potential in wound care strategies that target xCT/ferroptosis axes (zhang2024theroleof pages 1-2).

Expert opinions and analysis (authoritative sources)
- Transporter-targeted therapy analysis: Jakobsen and Nielsen (2024) provide a broad pharmacology perspective, integrating structural references, inhibitor classes, and cancer relevance; they underscore xCT’s centrality to GSH metabolism and ferroptosis and the need for selectivity and structural guidance in inhibitor design (jakobsen2024exploringaminoacid pages 30-31, jakobsen2024exploringaminoacid pages 12-14).
- Disease-focused perspectives: Reviews in HCC and ovarian cancer converge on SLC7A11 upregulation and chemoresistance, recommending ferroptosis-based strategies; these align with mechanistic understanding of GSH/GPX4 dependency (li2024slc7a11inhepatocellular pages 1-2, fantone2024roleofslc7a11xct pages 1-2).
- Mechanistic integration: The disulfidptosis review (2025) frames SLC7A11 as a nexus between ferroptosis resistance and disulfide-stress sensitivity under metabolic stress, offering a coherent conceptual model for context-dependent therapeutic exploitation (qiu2025slc7a11asa pages 1-3).

Relevant statistics and data from recent studies
- Transport kinetics: Approximate Km values summarized in 2024 synthesis: cystine ~50 µM, glutamate ~200 µM; antiporter stoichiometry ~1:1 (jakobsen2024exploringaminoacid pages 12-14).
- Expression patterns: 2024 transporter review and disease reviews compile tissue/cancer expression and associations with prognosis (e.g., upregulation in HCC and ovarian cancer correlating with therapy resistance), although specific cohort percentages vary by study; the reviews provide curated references and emphasize frequent overexpression in aggressive disease (li2024slc7a11inhepatocellular pages 1-2, fantone2024roleofslc7a11xct pages 1-2, jakobsen2024exploringaminoacid pages 12-14).
- Trafficking/PTM quantitative observations: Mutation at K473 reduces apparent molecular mass (by ~7.5 kDa for K473R and ~4 kDa for K473Q) and markedly lowers surface expression and transport activity in cell models (koppin2024lysine473regulates pages 1-2).

Biochemical function and localization (precise role and site of action)
- Substrates and specificity: SLC7A11 mediates L-cystine uptake in exchange for L-glutamate. The imported cystine is immediately reduced to cysteine intracellularly; the transporter’s specificity underpins cysteine supply for GSH synthesis (jakobsen2024exploringaminoacid pages 12-14).
- Mechanism: Obligate antiport of glutamate and cystine, Na+-independent, consistent with APC family transporters; this conserves redox balance by ensuring cysteine availability under oxidative and nutrient stress (jakobsen2024exploringaminoacid pages 12-14, jakobsen2024exploringaminoacid pages 28-30).
- Localization: Predominantly at the plasma membrane as a heterodimer with SLC3A2; trafficking is regulated by PTMs (e.g., K473 state) and requires proper glycosylation of the complex to reach the surface (koppin2024lysine473regulates pages 1-2, jakobsen2024exploringaminoacid pages 12-14).

Regulation (expression and protein stability)
- Transcriptional control: SLC7A11 is stress-inducible via NRF2 and ATF4 pathways (e.g., electrophile/oxidative and amino-acid deprivation responses) and is repressed by p53, BAP1 and ATF3 in cancer contexts, as compiled by 2024 reviews (jakobsen2024exploringaminoacid pages 28-30, li2024slc7a11inhepatocellular pages 1-2, zhang2024theroleof pages 1-2).
- Post-translational/trafficking control: K473-dependent acetylation/deacetylation dynamics regulate ER–Golgi progression; lack of appropriate modification leads to ER retention and inactivity (koppin2024lysine473regulates pages 1-2). Proper assembly with glycosylated SLC3A2 is necessary for membrane stability and transporter function (koppin2024lysine473regulates pages 1-2, jakobsen2024exploringaminoacid pages 12-14).

Pathway context (glutathione, redox homeostasis, ferroptosis, disulfidptosis)
- GSH/GPX4 axis: SLC7A11-driven cystine import sustains GSH levels, enabling GPX4 to detoxify lipid hydroperoxides; blocking SLC7A11 reduces GSH and induces ferroptosis (li2024slc7a11inhepatocellular pages 1-2, jakobsen2024exploringaminoacid pages 12-14).
- Disulfidptosis: High SLC7A11 flux under glucose deprivation can deplete reducing equivalents (NADPH), promoting disulfide accumulation and actin cytoskeleton collapse, defining the disulfidptosis phenotype (qiu2025slc7a11asa pages 1-3).

Therapeutic strategies and inhibitors
- Small-molecule inhibitors: Erastin and sulfasalazine remain canonical system xc− inhibitors for ferroptosis induction; sorafenib is discussed in HCC contexts as modulating ferroptosis pathways (li2024slc7a11inhepatocellular pages 1-2, jakobsen2024exploringaminoacid pages 12-14, fantone2024roleofslc7a11xct pages 1-2). Reviews emphasize ongoing structure-guided discovery and the need for specificity (jakobsen2024exploringaminoacid pages 30-31, jakobsen2024exploringaminoacid pages 12-14).
- Translational considerations: While a sulfasalazine glioma trial was terminated, multiple disease reviews in 2024 advocate for patient stratification by SLC7A11 status and rational combinations (e.g., with therapies that increase oxidative stress) to harness ferroptosis therapeutically (jakobsen2024exploringaminoacid pages 30-31, li2024slc7a11inhepatocellular pages 1-2, fantone2024roleofslc7a11xct pages 1-2).

Concise evidence map of key 2023–2024 sources
| Topic | Specific claim | Mechanistic / quantitative detail | Source (authors, year) | Journal | DOI / URL | Pub date |
|---|---|---|---|---|---|---|
| Identity & complex with SLC3A2 | SLC7A11 (xCT) is the light-chain catalytic subunit of system Xc- and forms a disulfide-linked heterodimer with SLC3A2 (4F2hc) | Multi-pass (≈12 TM) membrane protein (~501 aa) that couples to glycosylated SLC3A2 for plasma-membrane localization (heteromeric amino-acid transporter) | Jakobsen S., Nielsen C.U., 2024 (jakobsen2024exploringaminoacid pages 12-14) | Pharmaceutics | https://doi.org/10.3390/pharmaceutics16020197 (jakobsen2024exploringaminoacid pages 12-14) | Jan 2024 |
| Antiporter function & 1:1 stoichiometry and Km values | System Xc- exchanges extracellular L-cystine for intracellular L-glutamate at ~1:1 stoichiometry | Reported Km: cystine ≈ 50 μM; glutamate ≈ 200 μM; Na+-independent antiporter (cystine import → intracellular reduction to cysteine) | Jakobsen S., Nielsen C.U., 2024 (jakobsen2024exploringaminoacid pages 12-14), supporting reviews (jakobsen2024exploringaminoacid pages 28-30) | Pharmaceutics / reviews | https://doi.org/10.3390/pharmaceutics16020197 (jakobsen2024exploringaminoacid pages 12-14) | Jan 2024 |
| Glutathione / GPX4 → ferroptosis pathway role | SLC7A11 supplies cystine for GSH synthesis; GSH is cofactor for GPX4 that prevents lipid peroxidation; SLC7A11 inhibition depletes GSH and induces ferroptosis | Functional linkage: cystine import → cysteine → GSH synthesis → GPX4 activity; genetic/pharmacologic blockade triggers iron-dependent lipid-peroxidation cell death (ferroptosis) | Li T. et al., 2024 (li2024slc7a11inhepatocellular pages 1-2); Jakobsen 2024 (jakobsen2024exploringaminoacid pages 12-14) | Am J Cancer Res; Pharmaceutics | Li: https://doi.org/10.62347/kgcl7357 (li2024slc7a11inhepatocellular pages 1-2); Jakobsen DOI above (jakobsen2024exploringaminoacid pages 12-14) | Jan 2024 |
| Regulation (NRF2 / ATF4 / p53 / BAP1 / ATF3) | SLC7A11 transcription is induced by NRF2/ATF4 (stress response) and repressed by p53, BAP1 and ATF3 (epigenetic/transcriptional control) — some interactions are directly demonstrated, others summarized in reviews | Examples: electrophile/oxidative stress → p62–Keap1→NRF2 → SLC7A11 induction; p53/BAP1 reported to repress SLC7A11 in cancer contexts (some mechanistic/ChIP evidence cited in reviews) | Jakobsen 2024 (jakobsen2024exploringaminoacid pages 28-30, jakobsen2024exploringaminoacid pages 12-14); Li 2024 (li2024slc7a11inhepatocellular pages 1-2); Zhang W. 2024 (zhang2024theroleof pages 1-2) | Pharmaceutics; Am J Cancer Res; Frontiers Immunol | Jakobsen DOI (jakobsen2024exploringaminoacid pages 12-14); Li DOI (li2024slc7a11inhepatocellular pages 1-2); https://doi.org/10.3389/fimmu.2024.1467531 (zhang2024theroleof pages 1-2) | 2024 (reviews) |
| Trafficking / post‑translational modifications (PTMs) | C-terminal Lys473 regulates biosynthetic progression; K473 mutation impairs glycosylation, causes ER retention and loss of plasma‑membrane activity; glycosylation required for proper trafficking and function | K473R → loss of N-/O-glycosylation, ER sequestration and loss of transport activity; glycosylation of partner heavy chain (SLC3A2) also important for membrane stability (trafficking dependent) | Koppin A., Chase L., 2024 (koppin2024lysine473regulates pages 1-2) | Int J Mol Sci | https://doi.org/10.3390/ijms251910271 (koppin2024lysine473regulates pages 1-2) | 24 Sep 2024 |
| Structural insights / cryo‑EM mention | Cryo‑EM structures of SLC7A11–SLC3A2 complex have been reported / referenced in recent structural reviews; structural studies inform inhibitor binding hypotheses (e.g., erastin interaction) | Cryo‑EM resolved heterodimer architecture used to infer substrate path and inhibitor binding sites; structural data cited in 2024 transporter reviews | Jakobsen 2024 (jakobsen2024exploringaminoacid pages 12-14), supporting review citations (jakobsen2024exploringaminoacid pages 28-30) | Pharmaceutics / reviews | https://doi.org/10.3390/pharmaceutics16020197 (jakobsen2024exploringaminoacid pages 12-14) | Jan 2024 |
| Therapeutic inhibitors & oncology context (erastin, sulfasalazine, sorafenib, new leads) | Small molecules (erastin, sulfasalazine, sorafenib among others) inhibit xCT-mediated cystine import, sensitizing tumors to ferroptosis; inhibitor discovery remains active with structure‑based screens | Preclinical/repurposing evidence across cancer models; sulfasalazine and erastin widely used in labs to inhibit system Xc-; inhibitor design/virtual screening efforts reported 2023–2024 | Jakobsen 2024 (jakobsen2024exploringaminoacid pages 12-14), Li T. 2024 (li2024slc7a11inhepatocellular pages 1-2), Fantone 2024 (fantone2024roleofslc7a11xct pages 1-2) | Pharmaceutics; Am J Cancer Res; Int J Mol Sci | Jakobsen DOI (jakobsen2024exploringaminoacid pages 12-14); Li DOI (li2024slc7a11inhepatocellular pages 1-2); Fantone https://doi.org/10.3390/ijms25010587 (fantone2024roleofslc7a11xct pages 1-2) | 2024 |
| Disease applications (HCC, ovarian cancer, diabetic wound) | SLC7A11 overexpression associated with poor prognosis / therapy resistance in HCC and ovarian cancer; modulation relevant to diabetic wound healing via redox / immune pathways | Reviews and disease-focused studies describe associations (overexpression, chemoresistance) and propose SLC7A11 targeting to induce ferroptosis in tumors or modulate oxidative stress in wounds | Li T. et al., 2024 (HCC) (li2024slc7a11inhepatocellular pages 1-2); Fantone S. et al., 2024 (ovarian) (fantone2024roleofslc7a11xct pages 1-2); Zhang W. et al., 2024 (diabetic wound) (zhang2024theroleof pages 1-2) | Am J Cancer Res; Int J Mol Sci; Frontiers Immunol | Li DOI (li2024slc7a11inhepatocellular pages 1-2); Fantone https://doi.org/10.3390/ijms25010587 (fantone2024roleofslc7a11xct pages 1-2); Zhang https://doi.org/10.3389/fimmu.2024.1467531 (zhang2024theroleof pages 1-2) | 2024 |
| Disulfidptosis linkage (mechanistic note; 2025 source) | High SLC7A11 activity under glucose deprivation can lead to NADPH consumption and disulfide stress, triggering disulfidptosis (distinct metabolic cell death) — reported in a 2025 review linking ferroptosis and disulfidptosis | Mechanistic proposal: cystine import/processing consumes reducing equivalents → disulfide accumulation in actin cytoskeleton → disulfidptosis; conceptually relevant to SLC7A11 biology (see Qiu et al., 2025) | Qiu H. et al., 2025 (qiu2025slc7a11asa pages 1-3) | Cell Commun Signal | https://doi.org/10.1186/s12964-025-02447-x (qiu2025slc7a11asa pages 1-3) | Oct 2025 |

Table: Compact, source‑mapped table linking key mechanistic claims about human SLC7A11 (xCT) to 2023–2024 (and a 2025 mechanistic review) references, showing where quantitative details, structural, regulatory, trafficking and therapeutic evidence were reported (context IDs cited for traceability).

Citations with URLs and dates
- Jakobsen S., Nielsen C.U. Exploring amino acid transporters as therapeutic targets for cancer: inhibitor structures, selectivity, discovery approaches. Pharmaceutics 16:197 (Jan 2024). URL: https://doi.org/10.3390/pharmaceutics16020197 (jakobsen2024exploringaminoacid pages 12-14, jakobsen2024exploringaminoacid pages 30-31, jakobsen2024exploringaminoacid pages 28-30).
- Li T., Yi J., Wu H., Wang K., Zhou B. SLC7A11 in hepatocellular carcinoma: mechanisms, regulation, clinical significance. Am J Cancer Res 14(5):2326–2342 (Jan 2024). URL: https://doi.org/10.62347/kgcl7357 (li2024slc7a11inhepatocellular pages 1-2).
- Fantone S. et al. Role of SLC7A11/xCT in ovarian cancer. Int J Mol Sci 25:587 (Jan 2024). URL: https://doi.org/10.3390/ijms25010587 (fantone2024roleofslc7a11xct pages 1-2).
- Zhang W. et al. The role of SLC7A11 in diabetic wound healing. Front Immunol (Sep 3, 2024). URL: https://doi.org/10.3389/fimmu.2024.1467531 (zhang2024theroleof pages 1-2).
- Koppin A., Chase L. Lysine 473 regulates SLC7A11 progression through the secretory pathway. Int J Mol Sci (Sep 24, 2024). URL: https://doi.org/10.3390/ijms251910271 (koppin2024lysine473regulates pages 1-2).
- Qiu H. et al. SLC7A11 as a bridge between ferroptosis and disulfidptosis. Cell Commun Signal (Oct 2025). URL: https://doi.org/10.1186/s12964-025-02447-x (mechanistic linkage, later publication) (qiu2025slc7a11asa pages 1-3).

Conclusions
Human SLC7A11 (xCT; Q9UPY5) is a 12-TM APC-family transporter that forms a disulfide-linked heterodimer with SLC3A2 to mediate Na+-independent 1:1 L-cystine/L-glutamate exchange at the plasma membrane. This transport reaction supplies cysteine for GSH synthesis and underpins GPX4 activity, making SLC7A11 a gatekeeper of lipid-peroxidation control and ferroptosis resistance. Recent work refines our understanding of xCT trafficking and PTM regulation (e.g., K473-dependent ER–Golgi progression), while structural studies (cryo-EM) inform substrate/inhibitor interactions. 2024 disease reviews and pharmacology syntheses converge on SLC7A11 as a therapeutic target in cancer—particularly HCC and ovarian cancer—and in non-oncologic conditions such as diabetic wound healing. Real-world translation remains emergent; future efforts emphasize selective inhibitor design, rational combinations that elevate oxidative stress, biomarker-guided patient selection, and nuanced appreciation of context-dependent outcomes (including potential susceptibility to disulfidptosis under metabolic stress) (jakobsen2024exploringaminoacid pages 12-14, li2024slc7a11inhepatocellular pages 1-2, fantone2024roleofslc7a11xct pages 1-2, koppin2024lysine473regulates pages 1-2, qiu2025slc7a11asa pages 1-3).

References

(jakobsen2024exploringaminoacid pages 12-14): Sebastian Jakobsen and Carsten Uhd Nielsen. Exploring amino acid transporters as therapeutic targets for cancer: an examination of inhibitor structures, selectivity issues, and discovery approaches. Pharmaceutics, 16:197, Jan 2024. URL: https://doi.org/10.3390/pharmaceutics16020197, doi:10.3390/pharmaceutics16020197. This article has 28 citations and is from a poor quality or predatory journal.
(jakobsen2024exploringaminoacid pages 28-30): Sebastian Jakobsen and Carsten Uhd Nielsen. Exploring amino acid transporters as therapeutic targets for cancer: an examination of inhibitor structures, selectivity issues, and discovery approaches. Pharmaceutics, 16:197, Jan 2024. URL: https://doi.org/10.3390/pharmaceutics16020197, doi:10.3390/pharmaceutics16020197. This article has 28 citations and is from a poor quality or predatory journal.
(zhang2024theroleof pages 1-2): Wei Zhang, Jiawei Feng, Yiming Ni, Gen Li, Yuqing Wang, Yemin Cao, Mingmei Zhou, and Cheng Zhao. The role of slc7a11 in diabetic wound healing: novel insights and new therapeutic strategies. Frontiers in Immunology, Sep 2024. URL: https://doi.org/10.3389/fimmu.2024.1467531, doi:10.3389/fimmu.2024.1467531. This article has 9 citations and is from a peer-reviewed journal.
(li2024slc7a11inhepatocellular pages 1-2): Tianze Li, Jianwei Yi, Huajun Wu, Kai Wang, and Binghai Zhou. Slc7a11 in hepatocellular carcinoma: potential mechanisms, regulation, and clinical significance. American journal of cancer research, 14 5:2326-2342, Jan 2024. URL: https://doi.org/10.62347/kgcl7357, doi:10.62347/kgcl7357. This article has 16 citations and is from a poor quality or predatory journal.
(qiu2025slc7a11asa pages 1-3): Hui Qiu, Jing Liu, Nan Shao, Juanjuan Zhao, Chao Chen, Yuanye Jiang, Xu Zhao, and Lin Xu. Slc7a11 as a bridge between ferroptosis and disulfidptosis: a promising target for tumor treatment. Cell Communication and Signaling, Oct 2025. URL: https://doi.org/10.1186/s12964-025-02447-x, doi:10.1186/s12964-025-02447-x. This article has 0 citations and is from a peer-reviewed journal.
(jakobsen2024exploringaminoacid pages 30-31): Sebastian Jakobsen and Carsten Uhd Nielsen. Exploring amino acid transporters as therapeutic targets for cancer: an examination of inhibitor structures, selectivity issues, and discovery approaches. Pharmaceutics, 16:197, Jan 2024. URL: https://doi.org/10.3390/pharmaceutics16020197, doi:10.3390/pharmaceutics16020197. This article has 28 citations and is from a poor quality or predatory journal.
(fantone2024roleofslc7a11xct pages 1-2): Sonia Fantone, Federica Piani, Fabiola Olivieri, Maria Rita Rippo, Angelo Sirico, Nicoletta Di Simone, Daniela Marzioni, and Giovanni Tossetta. Role of slc7a11/xct in ovarian cancer. International Journal of Molecular Sciences, 25:587, Jan 2024. URL: https://doi.org/10.3390/ijms25010587, doi:10.3390/ijms25010587. This article has 86 citations and is from a poor quality or predatory journal.
(koppin2024lysine473regulates pages 1-2): Anna Koppin and Leah Chase. Lysine 473 regulates the progression of slc7a11, the cystine/glutamate exchanger, through the secretory pathway. International Journal of Molecular Sciences, Sep 2024. URL: https://doi.org/10.3390/ijms251910271, doi:10.3390/ijms251910271. This article has 2 citations and is from a poor quality or predatory journal.

Citations

jakobsen2024exploringaminoacid pages 12-14
jakobsen2024exploringaminoacid pages 30-31
zhang2024theroleof pages 1-2
jakobsen2024exploringaminoacid pages 28-30
https://doi.org/10.3390/pharmaceutics16020197
https://doi.org/10.62347/kgcl7357
https://doi.org/10.3389/fimmu.2024.1467531
https://doi.org/10.3390/ijms251910271
https://doi.org/10.3390/ijms25010587
https://doi.org/10.1186/s12964-025-02447-x
https://doi.org/10.3390/pharmaceutics16020197,
https://doi.org/10.3389/fimmu.2024.1467531,
https://doi.org/10.62347/kgcl7357,
https://doi.org/10.1186/s12964-025-02447-x,
https://doi.org/10.3390/ijms25010587,
https://doi.org/10.3390/ijms251910271,

📄 View Raw YAML

id: Q9UPY5
gene_symbol: SLC7A11
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'SLC7A11 (xCT) is the light chain (catalytic subunit) of system xc-,
  a heterodimeric cystine/glutamate antiporter that forms a disulfide-linked heterodimer
  with SLC3A2 (4F2hc, the heavy chain). It mediates Na+-independent, electroneutral
  exchange of extracellular L-cystine for intracellular L-glutamate at ~1:1 stoichiometry
  (Km ~43-110 uM for cystine, ~48-224 uM for glutamate). The imported cystine is reduced
  intracellularly to cysteine, providing the rate-limiting substrate for glutathione
  (GSH) synthesis. This positions SLC7A11 as a critical regulator of cellular redox
  homeostasis and a suppressor of ferroptosis through the GSH/GPX4 axis. Recent studies
  have identified additional functions including L-kynurenine transport and novel
  lysosomal proton channel activity.

  '
existing_annotations:
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:11417227
  review:
    summary: 'This is the primary molecular function of SLC7A11. PMID:11417227 (Bassi
      et al., 2001) directly demonstrated that human xCT co-expressed with 4F2hc mediates
      Na+-independent cystine/glutamate antiport with Km values of 43 uM for cystine
      and 92 uM for glutamate.

      '
    action: ACCEPT
    reason: 'Core molecular function established by direct transport assays in reconstituted
      systems. Multiple studies confirm this antiporter activity with defined kinetics.

      '
    supported_by:
    - reference_id: PMID:11417227
      supporting_text: The amino acid transport activity induced by the co-expression
        of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific
        for L-cystine, L-glutamate and L-aspartate
    - reference_id: file:human/SLC7A11/SLC7A11-deep-research-falcon.md
      supporting_text: System xc− exchanges extracellular L-cystine for intracellular
        L-glutamate at approximately 1:1 stoichiometry, enabling cystine import that
        is reduced intracellularly to cysteine for glutathione (GSH) synthesis; reported
        Km values are ~50 µM (cystine) and ~200 µM (glutamate)
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:15151999
  review:
    summary: 'PMID:15151999 (Gasol et al., 2004) characterized membrane topology and
      transport function, reporting Km of 110 uM for cystine and 224 uM for glutamate.

      '
    action: ACCEPT
    reason: 'Confirms core antiporter activity with detailed kinetic characterization
      and membrane topology analysis.

      '
    supported_by:
    - reference_id: PMID:15151999
      supporting_text: 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine
        and L-glutamate (system x(c)(-))
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:34120018
  review:
    summary: 'PMID:34120018 (Lofthouse et al., 2021) demonstrated xCT-mediated cystine/glutamate
      antiport in human placenta, including N-acetylcysteine transport.

      '
    action: ACCEPT
    reason: 'Confirms antiporter activity in physiologically relevant tissue context
      (placenta).

      '
    supported_by:
    - reference_id: PMID:34120018
      supporting_text: Maternoplacental N-acetylcysteine administration stimulated
        intracellular glutamate efflux suggesting a role of the exchange transporter
        xCT
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: RCA
  original_reference_id: PMID:34880232
  review:
    summary: 'PMID:34880232 (Parker et al., 2021) provided cryo-EM structure of xCT-4F2hc
      complex with L-glutamate bound, revealing molecular basis of antiporter function.

      '
    action: ACCEPT
    reason: 'Structural evidence confirming antiporter mechanism with substrate-bound
      structure.

      '
    supported_by:
    - reference_id: PMID:34880232
      supporting_text: Here we present the cryo-EM structure of system xc- in both
        the apo and glutamate bound states
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:35352032
  review:
    summary: 'PMID:35352032 (Yan et al., 2022) provided erastin-bound xCT-4F2hc structure
      showing inhibitor binding site and transport mechanism.

      '
    action: ACCEPT
    reason: 'Structural and functional evidence for antiporter activity with inhibitor
      binding site.

      '
    supported_by:
    - reference_id: PMID:35352032
      supporting_text: "The small-molecule compound erastin induces ferroptosis via\
        \ inhibiting the cystine-glutamate antiporter system xc\u2013"
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:35245456
  review:
    summary: 'PMID:35245456 (Fiore et al., 2022) confirmed cystine:glutamate antiport
      while also discovering kynurenine transport capability.

      '
    action: ACCEPT
    reason: 'Confirms core antiporter function in context of expanded substrate repertoire
      study.

      '
    supported_by:
    - reference_id: PMID:35245456
      supporting_text: We show that this effect requires KYN export from IDO1-expressing
        cells, which is then available for non-IDO1-expressing cells via SLC7A11,
        the central transporter involved in ferroptosis suppression
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 confirmed canonical cystine:glutamate antiporter function
      while discovering novel lysosomal proton channel activity.

      '
    action: ACCEPT
    reason: 'Confirms core antiporter function in context of study expanding known
      functions.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
        erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
        and glutamate
- term:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  evidence_type: TAS
  original_reference_id: PMID:10206947
  review:
    summary: 'PMID:10206947 (Sato et al., 1999) was the original cloning paper identifying
      xCT as the light chain of system xc-.

      '
    action: ACCEPT
    reason: 'Foundational paper establishing identity and function of xCT.

      '
    supported_by:
    - reference_id: PMID:10206947
      supporting_text: The latter protein, named xCT, showed a significant homology
        with those recently reported to mediate cationic or zwitterionic amino acid
        transport when co-expressed with 4F2hc
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Automated annotation based on ARBA rules and orthology. L-cystine transport
      is the primary biological process mediated by SLC7A11.

      '
    action: ACCEPT
    reason: 'Core biological process - IEA is redundant with multiple IDA annotations
      but correctly captures the function.

      '
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:11417227
  review:
    summary: 'Direct demonstration of L-cystine uptake via xCT/4F2hc complex with
      Km = 43 uM.

      '
    action: ACCEPT
    reason: 'Core biological process with direct kinetic evidence.

      '
    supported_by:
    - reference_id: PMID:11417227
      supporting_text: The amino acid transport activity induced by the co-expression
        of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific
        for L-cystine, L-glutamate and L-aspartate
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:15151999
  review:
    summary: 'Confirmed cystine transport with Km = 110 uM in detailed topology study.

      '
    action: ACCEPT
    reason: 'Core biological process confirmed with kinetic parameters.

      '
    supported_by:
    - reference_id: PMID:15151999
      supporting_text: 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine
        and L-glutamate (system x(c)(-))
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:34880232
  review:
    summary: 'Structural study confirming cystine transport mechanism.

      '
    action: ACCEPT
    reason: 'Core biological process supported by structural evidence.

      '
    supported_by:
    - reference_id: PMID:34880232
      supporting_text: "Under redox stress conditions mammalian cells use a specific\
        \ system to increase cystine uptake to increase GSH synthesis, termed system\
        \ xc\u2212 a dedicated cystine-glutamate antiporter"
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:35352032
  review:
    summary: 'Confirmed cystine transport in context of erastin inhibition study.

      '
    action: ACCEPT
    reason: 'Core biological process with inhibitor sensitivity data.

      '
    supported_by:
    - reference_id: PMID:35352032
      supporting_text: inhibiting xCT impairs cystine uptake, causing an accumulation
        of ROS and suppressing tumor growth
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:11133847
  review:
    summary: 'PMID:11133847 (Bridges et al., 2001) characterized xCT function in retinal
      pigment epithelial cells.

      '
    action: ACCEPT
    reason: 'Core biological process demonstrated in RPE cells.

      '
    supported_by:
    - reference_id: PMID:11133847
      supporting_text: Coexpression of human xCT with 4F2hc in HeLa cells leads to
        the induction of cystine and glutamate uptake with characteristics similar
        to that of x(c)(-)
- term:
    id: GO:0015811
    label: L-cystine transport
  evidence_type: IDA
  original_reference_id: PMID:11213471
  review:
    summary: 'PMID:11213471 (Sato et al., 2000) original molecular cloning paper confirming
      cystine transport function.

      '
    action: ACCEPT
    reason: 'Foundational paper establishing cystine transport function.

      '
    supported_by:
    - reference_id: PMID:11213471
      supporting_text: Transport of system xc- is an exchange agency with high specificity
        for anionic form of cystine and glutamate
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'ARBA annotation capturing glutamate export function of the antiporter.

      '
    action: ACCEPT
    reason: 'Core biological process - glutamate efflux is integral to antiporter
      mechanism.

      '
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11417227
  review:
    summary: 'Direct demonstration of glutamate efflux coupled to cystine import with
      Km = 92 uM.

      '
    action: ACCEPT
    reason: 'Core biological process with kinetic evidence.

      '
    supported_by:
    - reference_id: PMID:11417227
      supporting_text: This activity also functioned in an exchange mode (e.g. cystine/glutamate)
        with a substrate stoichiometry of 1:1
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:15151999
  review:
    summary: 'Glutamate transport confirmed with Km = 224 uM.

      '
    action: ACCEPT
    reason: 'Core biological process with kinetic parameters.

      '
    supported_by:
    - reference_id: PMID:15151999
      supporting_text: 4F2hc/xCT elicits sodium-independent exchange of anionic L-cysteine
        and L-glutamate (system x(c)(-))
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:34880232
  review:
    summary: 'Structural study with glutamate-bound structure.

      '
    action: ACCEPT
    reason: 'Core biological process with structural evidence of glutamate binding.

      '
    supported_by:
    - reference_id: PMID:34880232
      supporting_text: Here we present the cryo-EM structure of system xc- in both
        the apo and glutamate bound states
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:35352032
  review:
    summary: 'Glutamate transport in context of erastin inhibition.

      '
    action: ACCEPT
    reason: 'Core biological process confirmed.

      '
    supported_by:
    - reference_id: PMID:35352032
      supporting_text: "The small-molecule compound erastin induces ferroptosis via\
        \ inhibiting the cystine-glutamate antiporter system xc\u2013"
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11133847
  review:
    summary: 'Glutamate transport in RPE cells.

      '
    action: ACCEPT
    reason: 'Core biological process in physiological context.

      '
    supported_by:
    - reference_id: PMID:11133847
      supporting_text: the uptake of glutamate in the absence of Na(+) occurs exclusively
        via x(c)(-)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Automated annotation for plasma membrane localization.

      '
    action: ACCEPT
    reason: 'Core localization - xCT functions primarily at the plasma membrane.

      '
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:11417227
  review:
    summary: 'Direct demonstration of plasma membrane localization.

      '
    action: ACCEPT
    reason: 'Core localization established by immunofluorescence and functional studies.

      '
    supported_by:
    - reference_id: PMID:11417227
      supporting_text: The amino acid transport activity induced by the co-expression
        of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific
        for L-cystine, L-glutamate and L-aspartate
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15151999
  review:
    summary: 'Membrane topology study confirming plasma membrane localization.

      '
    action: ACCEPT
    reason: 'Core localization with detailed topology mapping.

      '
    supported_by:
    - reference_id: PMID:15151999
      supporting_text: we propose a topological model for xCT of 12 transmembrane
        domains with the N and C termini located inside the cell
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:40246981
  review:
    summary: 'PMID:40246981 studied galectin-13-mediated regulation of SLC7A11 membrane
      localization.

      '
    action: ACCEPT
    reason: 'Confirms plasma membrane as functional location.

      '
    supported_by:
    - reference_id: PMID:40246981
      supporting_text: Galectin-13, which binds to CD44 and inhibits the plasma membrane
        localization of SLC7A11 in neighboring cells, thereby accelerating neighboring
        cell death and promoting ferroptosis propagation
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IPI
  original_reference_id: PMID:34880232
  review:
    summary: 'Co-localization with SLC3A2 at plasma membrane in structural study.

      '
    action: ACCEPT
    reason: 'Core localization confirmed through complex formation.

      '
    supported_by:
    - reference_id: PMID:34880232
      supporting_text: The light subunit of human xc- transporter, xCT, (SLC7A11),
        consists of 12 transmembrane helices (TMs)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-375131
  review:
    summary: 'Reactome pathway annotation for basigin interactions at plasma membrane.

      '
    action: ACCEPT
    reason: 'Core localization supported by pathway database.

      '
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-378513
  review:
    summary: 'Reactome pathway for SLC7A11-mediated cystine/glutamate exchange.

      '
    action: ACCEPT
    reason: 'Core localization in transport pathway context.

      '
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9761841
  review:
    summary: 'Reactome NFE2L2-dependent SLC7A11 expression pathway.

      '
    action: ACCEPT
    reason: 'Core localization in regulatory pathway context.

      '
- term:
    id: GO:0110076
    label: negative regulation of ferroptosis
  evidence_type: IDA
  original_reference_id: PMID:40246981
  review:
    summary: 'PMID:40246981 demonstrated that SLC7A11 suppresses ferroptosis; galectin-13
      reduces membrane SLC7A11 to propagate ferroptosis.

      '
    action: ACCEPT
    reason: 'Core function - SLC7A11 is a central suppressor of ferroptosis through
      cystine import and GSH/GPX4 pathway. This is one of the most well-established
      physiological consequences of xCT function.

      '
    supported_by:
    - reference_id: PMID:40246981
      supporting_text: Galectin-13, which binds to CD44 and inhibits the plasma membrane
        localization of SLC7A11 in neighboring cells, thereby accelerating neighboring
        cell death and promoting ferroptosis propagation
- term:
    id: GO:0110076
    label: negative regulation of ferroptosis
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 confirmed anti-ferroptotic function while discovering
      lysosomal role.

      '
    action: ACCEPT
    reason: 'Core function confirmed in context of expanded functional characterization.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11 deficiency or inhibition caused lysosomal over-acidification,
        reduced degradation, accumulation of storage materials, and ferroptosis
- term:
    id: GO:0110076
    label: negative regulation of ferroptosis
  evidence_type: IDA
  original_reference_id: PMID:35245456
  review:
    summary: 'PMID:35245456 showed kynurenine import via SLC7A11 propagates anti-ferroptotic
      signaling.

      '
    action: ACCEPT
    reason: 'Core function demonstrated through novel kynurenine pathway.

      '
    supported_by:
    - reference_id: PMID:35245456
      supporting_text: We show that this effect requires KYN export from IDO1-expressing
        cells, which is then available for non-IDO1-expressing cells via SLC7A11,
        the central transporter involved in ferroptosis suppression
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'UniProt subcellular location annotation based on lysosomal membrane
      localization.

      '
    action: ACCEPT
    reason: 'Recently validated secondary localization - IDA evidence in PMID:40280132
      confirms lysosomal membrane localization.

      '
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 directly demonstrated SLC7A11 localization and function
      at lysosomal membranes where it acts as a proton channel.

      '
    action: ACCEPT
    reason: 'Novel secondary localization with direct experimental evidence for functional
      role at lysosomes.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
        erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
        and glutamate
- term:
    id: GO:0015252
    label: proton channel activity
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 discovered that SLC7A11 functions as an unconventional
      proton channel at lysosomal membranes, independent of its antiporter activity.

      '
    action: ACCEPT
    reason: 'Novel molecular function with direct experimental evidence. This represents
      a newly discovered activity distinct from the canonical antiporter function.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
        erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
        and glutamate
- term:
    id: GO:0022840
    label: leak channel activity
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 characterized SLC7A11 as having leak channel properties
      for protons at lysosomal membranes.

      '
    action: ACCEPT
    reason: 'Novel molecular function - proton leak channel activity at lysosomes.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
        erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
        and glutamate
- term:
    id: GO:0022840
    label: leak channel activity
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'Duplicate annotation in GOA - same evidence as above.

      '
    action: ACCEPT
    reason: 'Same evidence supports leak channel activity at lysosomes.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11 deficiency or inhibition caused lysosomal over-acidification,
        reduced degradation, accumulation of storage materials, and ferroptosis
- term:
    id: GO:0035752
    label: lysosomal lumen pH elevation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Ensembl Compara transfer from mouse ortholog.

      '
    action: ACCEPT
    reason: 'Supported by direct experimental evidence in PMID:40280132 demonstrating
      lysosomal pH elevation via proton channel activity.

      '
- term:
    id: GO:0035752
    label: lysosomal lumen pH elevation
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 demonstrated that SLC7A11 proton channel activity elevates
      lysosomal lumen pH.

      '
    action: ACCEPT
    reason: 'Novel biological process with direct experimental evidence.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11 deficiency or inhibition caused lysosomal over-acidification,
        reduced degradation, accumulation of storage materials, and ferroptosis
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'PMID:40280132 demonstrated proton transport activity at lysosomal membranes.

      '
    action: ACCEPT
    reason: 'Novel biological process supporting proton channel function discovery.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
        erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
        and glutamate
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:40280132
  review:
    summary: 'Duplicate annotation in GOA - same evidence as above.

      '
    action: ACCEPT
    reason: 'Same evidence supports proton transmembrane transport.

      '
    supported_by:
    - reference_id: PMID:40280132
      supporting_text: SLC7A11 deficiency or inhibition caused lysosomal over-acidification,
        reduced degradation, accumulation of storage materials, and ferroptosis
- term:
    id: GO:0140924
    label: L-kynurenine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:35245456
  review:
    summary: 'PMID:35245456 (Fiore et al., 2022) discovered that SLC7A11 imports L-kynurenine,
      a tryptophan metabolite, which propagates anti-ferroptotic signaling.

      '
    action: ACCEPT
    reason: 'Novel expanded substrate specificity with direct experimental evidence.
      Kynurenine import contributes to anti-ferroptotic function.

      '
    supported_by:
    - reference_id: PMID:35245456
      supporting_text: We show that this effect requires KYN export from IDO1-expressing
        cells, which is then available for non-IDO1-expressing cells via SLC7A11,
        the central transporter involved in ferroptosis suppression
- term:
    id: GO:0140926
    label: L-kynurenine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:35245456
  review:
    summary: 'PMID:35245456 demonstrated L-kynurenine transporter activity for SLC7A11.

      '
    action: ACCEPT
    reason: 'Novel molecular function - expanded substrate specificity beyond cystine/glutamate.

      '
    supported_by:
    - reference_id: PMID:35245456
      supporting_text: We show that this effect requires KYN export from IDO1-expressing
        cells, which is then available for non-IDO1-expressing cells via SLC7A11,
        the central transporter involved in ferroptosis suppression
- term:
    id: GO:0003333
    label: amino acid transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation from phylogenetic inference. While technically correct,
      this term is too general for a transporter with well-characterized substrate
      specificity.

      '
    action: MODIFY
    reason: 'Too general. SLC7A11 specifically transports L-cystine and L-glutamate
      as an antiporter, plus recently discovered L-kynurenine. The more specific terms
      GO:0015811 (L-cystine transport) and GO:0015813 (L-glutamate transmembrane transport)
      are more appropriate.

      '
    proposed_replacement_terms:
    - id: GO:0015811
      label: L-cystine transport
    - id: GO:0015813
      label: L-glutamate transmembrane transport
- term:
    id: GO:0015179
    label: L-amino acid transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation from phylogenetic inference. Too general for a transporter
      with well-characterized antiporter mechanism.

      '
    action: MODIFY
    reason: 'Too general. SLC7A11 has cystine:glutamate antiporter activity (GO:0015327),
      which is the appropriate specific term.

      '
    proposed_replacement_terms:
    - id: GO:0015327
      label: cystine:glutamate antiporter activity
- term:
    id: GO:0006865
    label: amino acid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'IEA from InterPro domain. Too general for well-characterized transporter.

      '
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Too general. The specific transport processes (L-cystine, L-glutamate)
      are better captured by more specific annotations already present.

      '
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'IEA from InterPro annotation. Too general for well-characterized antiporter.

      '
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Too general. GO:0015327 (cystine:glutamate antiporter activity) is the
      appropriate specific molecular function.

      '
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'IEA from InterPro. Very general biological process.

      '
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Too general. Specific transport processes are well-annotated.

      '
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'IEA annotation - too general for well-characterized membrane protein.

      '
    action: MODIFY
    reason: 'Too general. SLC7A11 is specifically localized to plasma membrane (primary)
      and lysosomal membrane (secondary), both of which are already annotated.

      '
    proposed_replacement_terms:
    - id: GO:0005886
      label: plasma membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:10206947
  review:
    summary: 'TAS annotation from original cloning paper. Too general.

      '
    action: MODIFY
    reason: 'Too general. Original paper demonstrated plasma membrane localization.

      '
    proposed_replacement_terms:
    - id: GO:0005886
      label: plasma membrane
    supported_by:
    - reference_id: PMID:10206947
      supporting_text: The latter protein, named xCT, showed a significant homology
        with those recently reported to mediate cationic or zwitterionic amino acid
        transport when co-expressed with 4F2hc
- term:
    id: GO:0089718
    label: amino acid import across plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:11417227
  review:
    summary: 'IDA from functional characterization study. While correct, this is less
      specific than the available terms.

      '
    action: MODIFY
    reason: 'Partially accurate but less specific. SLC7A11 imports L-cystine (not
      general amino acids) in exchange for glutamate export. GO:0015811 (L-cystine
      transport) is more specific and accurate.

      '
    proposed_replacement_terms:
    - id: GO:0015811
      label: L-cystine transport
    supported_by:
    - reference_id: PMID:11417227
      supporting_text: The amino acid transport activity induced by the co-expression
        of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific
        for L-cystine, L-glutamate and L-aspartate
- term:
    id: GO:0043067
    label: regulation of programmed cell death
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'ARBA annotation linking xCT to cell death regulation. Too vague.

      '
    action: MODIFY
    reason: 'Too general. SLC7A11 specifically negatively regulates ferroptosis (GO:0110076),
      a specific form of regulated cell death, through its role in GSH synthesis.

      '
    proposed_replacement_terms:
    - id: GO:0110076
      label: negative regulation of ferroptosis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21397861
  review:
    summary: 'PMID:21397861 (Ishimoto et al., 2011) showed CD44 variant interaction
      stabilizes xCT to regulate redox status in cancer cells.

      '
    action: REMOVE
    supported_by:
    - reference_id: PMID:21397861
      supporting_text: CD44 variant (CD44v) interacts with xCT, a glutamate-cystine
        transporter, and controls the intracellular level of reduced glutathione (GSH)
    reason: '"Protein binding" is uninformative per GO curation guidelines. The specific
      interaction with CD44 variant (CD44v) that stabilizes xCT would be better captured
      by a more specific term if available.

      '
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27173435
  review:
    summary: 'High-throughput protein interaction study.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative. HT-PPI studies often capture non-specific
      or context-dependent interactions.

      '
    supported_by:
    - reference_id: PMID:27173435
      supporting_text: Here we use affinity proteomics, genetics and cell biology
        to interrogate cilia
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: 'Binary protein interactome mapping study. Detected interactions with
      SLC3A2-4 isoform and keratin-associated proteins.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative. The SLC3A2 interaction is essential
      for function and better captured by complex formation annotations; keratin interactions
      may be non-specific.

      '
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Here we present a human 'all-by-all' reference interactome
        map of human binary protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: 'Binary protein interactome mapping study - additional interaction.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative per GO guidelines.

      '
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Here we present a human 'all-by-all' reference interactome
        map of human binary protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: 'Binary protein interactome mapping study - third interaction.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative per GO guidelines.

      '
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Here we present a human 'all-by-all' reference interactome
        map of human binary protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34880232
  review:
    summary: 'Structural study showing xCT-SLC3A2 complex. The interaction with SLC3A2
      is essential for function.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative. The xCT-SLC3A2 heterodimer formation
      is a functional requirement, not just protein binding. This is better represented
      by the complex formation in ComplexPortal (CPX-8190).

      '
    supported_by:
    - reference_id: PMID:34880232
      supporting_text: Here we present the cryo-EM structure of system xc- in both
        the apo and glutamate bound states
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: 'Multimodal cell maps study - high-throughput protein interaction data.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative per GO guidelines.

      '
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Here we construct a global map of human subcellular architecture
        through joint measurement of biophysical interactions and immunofluorescence
        images for over 5,100 proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40355756
  review:
    summary: 'Solute carrier superfamily interactome study detecting SLC7A11-SLC3A2
      interaction.

      '
    action: REMOVE
    reason: '"Protein binding" is uninformative. The SLC3A2 interaction is essential
      for heterodimer function and better captured by functional annotations.

      '
    supported_by:
    - reference_id: PMID:40355756
      supporting_text: Here, we used a systematic AP-MS approach to determine the
        protein interaction network of human solute carriers
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:25063885
  review:
    summary: 'PMID:25063885 detected SLC7A11 at cell surface in context of KSHV entry
      study.

      '
    action: ACCEPT
    reason: 'Acceptable localization annotation - cell surface is parent of plasma
      membrane and represents the functionally relevant location for the transporter.

      '
    supported_by:
    - reference_id: PMID:25063885
      supporting_text: the presence of CD98 and heparan sulfate (HS), the putative
        attachment receptor, was more variable
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'UniProt subcellular location annotation based on placental syncytiotrophoblast
      microvillus membrane localization.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Cell type-specific localization in placenta. This is a specialized localization,
      not universally applicable.

      '
    supported_by:
    - reference_id: PMID:34120018
      supporting_text: xCT, which was localised to the microvillous membrane of the
        placental syncytiotrophoblast
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Ensembl Compara transfer from mouse ortholog - intestinal/renal brush
      border.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Cell type-specific localization in polarized epithelia. Not the primary
      localization but relevant in specific tissue contexts.

      '
- term:
    id: GO:0045177
    label: apical part of cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Ensembl Compara transfer from mouse ortholog.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Cell type-specific localization in polarized cells. Consistent with brush
      border and microvillus membrane annotations.

      '
- term:
    id: GO:0097449
    label: astrocyte projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Ensembl Compara transfer - astrocyte-specific localization.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Cell type-specific localization in astrocytes. xCT is highly expressed
      in brain and plays important role in astrocyte glutamate release, but this is
      not the universal localization.

      '
- term:
    id: GO:0009636
    label: response to toxic substance
  evidence_type: IDA
  original_reference_id: PMID:17575980
  review:
    summary: 'PMID:17575980 examined differential expression of intestinal transporters
      in cholera patients, showing xCT involvement in response.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Context-specific response - xCT expression changes in response to toxic
      insults/disease states as part of oxidative stress response, but this is not
      the core function.

      '
    supported_by:
    - reference_id: PMID:17575980
      supporting_text: Two amino acid transporters, SLC7A11 and SLC6A14, were upregulated
        in acute cholera patients compared to convalescence
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10206947
  title: Cloning and expression of a plasma membrane cystine/glutamate exchange transporter
    composed of two distinct proteins.
  findings:
  - statement: Original cloning identified xCT as the light chain forming heterodimer
      with 4F2hc for system xc- activity
    supporting_text: The latter protein, named xCT, showed a significant homology
      with those recently reported to mediate cationic or zwitterionic amino acid
      transport when co-expressed with 4F2hc
- id: PMID:11133847
  title: Structure, function, and regulation of human cystine/glutamate transporter
    in retinal pigment epithelial cells.
  findings: []
- id: PMID:11213471
  title: Molecular cloning and expression of human xCT, the light chain of amino acid
    transport system xc-.
  findings: []
- id: PMID:11417227
  title: Identification and characterisation of human xCT that co-expresses, with
    4F2 heavy chain, the amino acid transport activity system xc-.
  findings:
  - statement: Demonstrated Na+-independent transport activity specific for L-cystine,
      L-glutamate and L-aspartate
    supporting_text: The amino acid transport activity induced by the co-expression
      of human 4F2hc and xCT in Xenopus oocytes was sodium independent and specific
      for L-cystine, L-glutamate and L-aspartate
  - statement: Established 1:1 stoichiometry of cystine/glutamate exchange
    supporting_text: This activity also functioned in an exchange mode (e.g. cystine/glutamate)
      with a substrate stoichiometry of 1:1
- id: PMID:15151999
  title: Membrane topology of system xc- light subunit reveals a re-entrant loop with
    substrate-restricted accessibility.
  findings:
  - statement: Established 12-TM topology with intracellular N and C termini
    supporting_text: we propose a topological model for xCT of 12 transmembrane domains
      with the N and C termini located inside the cell
  - statement: Identified re-entrant loop with substrate-restricted accessibility
    supporting_text: Studies of biotinylation and accessibility to sulfhydryl reagents
      revealed a re-entrant loop within intracellular loops 2 and 3
- id: PMID:17575980
  title: Differential expression of intestinal membrane transporters in cholera patients.
  findings:
  - statement: SLC7A11 upregulated in acute cholera patients as part of response to
      toxic substance
    supporting_text: Two amino acid transporters, SLC7A11 and SLC6A14, were upregulated
      in acute cholera patients compared to convalescence
- id: PMID:21397861
  title: CD44 variant regulates redox status in cancer cells by stabilizing the xCT
    subunit of system xc(-) and thereby promotes tumor growth.
  findings:
  - statement: CD44 variant interacts with xCT and controls intracellular GSH levels
    supporting_text: CD44 variant (CD44v) interacts with xCT, a glutamate-cystine
      transporter, and controls the intracellular level of reduced glutathione (GSH)
  - statement: Ablation of CD44 induces loss of xCT from cell surface
    supporting_text: Ablation of CD44 induced loss of xCT from the cell surface and
      suppressed tumor growth in a transgenic mouse model of gastric cancer
- id: PMID:25063885
  title: "KSHV attachment and entry are dependent on \u03B1V\u03B23 integrin localized\
    \ to specific cell surface microdomains and do not correlate with the presence\
    \ of heparan sulfate."
  findings:
  - statement: CD98 detected at cell surface microdomains
    supporting_text: the presence of CD98 and heparan sulfate (HS), the putative attachment
      receptor, was more variable
- id: PMID:27173435
  title: An organelle-specific protein landscape identifies novel diseases and molecular
    mechanisms.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:34120018
  title: N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in
    human placenta.
  findings:
  - statement: xCT mediates N-acetylcysteine uptake in placenta
    supporting_text: This study suggests that xCT mediates N-acetylcysteine uptake
      into the placenta
  - statement: xCT localized to microvillous membrane of placental syncytiotrophoblast
    supporting_text: xCT, which was localised to the microvillous membrane of the
      placental syncytiotrophoblast
- id: PMID:34880232
  title: Molecular basis for redox control by the human cystine/glutamate antiporter
    system xc().
  findings:
  - statement: Cryo-EM structure of system xc- in apo and glutamate bound states
    supporting_text: Here we present the cryo-EM structure of system xc- in both the
      apo and glutamate bound states
  - statement: xCT consists of 12 transmembrane helices adopting canonical APC superfamily
      fold
    supporting_text: The light subunit of human xc- transporter, xCT, (SLC7A11), consists
      of 12 transmembrane helices (TMs)
  - statement: System xc- is a dedicated cystine-glutamate antiporter
    supporting_text: "Under redox stress conditions mammalian cells use a specific\
      \ system to increase cystine uptake to increase GSH synthesis, termed system\
      \ xc\u2212 a dedicated cystine-glutamate antiporter"
- id: PMID:35245456
  title: Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling.
  findings:
  - statement: SLC7A11 imports kynurenine which propagates anti-ferroptotic signaling
    supporting_text: We show that this effect requires KYN export from IDO1-expressing
      cells, which is then available for non-IDO1-expressing cells via SLC7A11, the
      central transporter involved in ferroptosis suppression
- id: PMID:35352032
  title: The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms
    underlying erastin-induced ferroptosis.
  findings:
  - statement: Erastin induces ferroptosis by inhibiting system xc-
    supporting_text: "The small-molecule compound erastin induces ferroptosis via\
      \ inhibiting the cystine-glutamate antiporter system xc\u2013"
  - statement: xCT regulates ferroptosis in multiple pathophysiological processes
    supporting_text: Recent studies have shown that xCT (SLC7A11) regulates ferroptosis
      in liver fibrosis, cardiomyopathy, and numerous other pathophysiological processes
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:40246981
  title: Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation.
  findings:
  - statement: Galectin-13 inhibits plasma membrane localization of SLC7A11 to promote
      ferroptosis
    supporting_text: Galectin-13, which binds to CD44 and inhibits the plasma membrane
      localization of SLC7A11 in neighboring cells, thereby accelerating neighboring
      cell death and promoting ferroptosis propagation
- id: PMID:40280132
  title: SLC7A11 is an unconventional H(+) transporter in lysosomes.
  findings:
  - statement: SLC7A11 mediates slow lysosomal H+ leak through cystine/glutamate flux
    supporting_text: SLC7A11, the protein target of the ferroptosis-inducing compound
      erastin, mediates a slow lysosomal H+ leak through downward flux of cystine
      and glutamate
  - statement: SLC7A11 deficiency causes lysosomal over-acidification and ferroptosis
    supporting_text: SLC7A11 deficiency or inhibition caused lysosomal over-acidification,
      reduced degradation, accumulation of storage materials, and ferroptosis
- id: PMID:40355756
  title: The solute carrier superfamily interactome.
  findings: []
- id: Reactome:R-HSA-375131
  title: Basigin binds CD98 complex
  findings: []
- id: Reactome:R-HSA-378513
  title: SLC7A11-mediated exchange of extracellular cysteine and cytosolic glutamate
  findings: []
- id: Reactome:R-HSA-9761841
  title: AcK-NFE2L2-dependent SLC7A11 expression
  findings: []
- id: file:human/SLC7A11/SLC7A11-deep-research-falcon.md
  title: Deep research report on SLC7A11
  findings:
  - statement: System xc− exchanges extracellular L-cystine for intracellular L-glutamate
      at ~1:1 stoichiometry to supply cysteine for GSH synthesis
    supporting_text: System xc− exchanges extracellular L-cystine for intracellular
      L-glutamate at approximately 1:1 stoichiometry, enabling cystine import that
      is reduced intracellularly to cysteine for glutathione (GSH) synthesis; reported
      Km values are ~50 µM (cystine) and ~200 µM (glutamate)
core_functions:
- description: 'Primary molecular function established by multiple structural and
    functional studies. SLC7A11 (xCT) forms a disulfide-linked heterodimer with SLC3A2
    (4F2hc) to mediate Na+-independent, electroneutral 1:1 exchange of extracellular
    L-cystine for intracellular L-glutamate. Km values: cystine ~43-110 uM, glutamate
    ~48-224 uM.

    '
  molecular_function:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  directly_involved_in:
  - id: GO:0015811
    label: L-cystine transport
  - id: GO:0015813
    label: L-glutamate transmembrane transport
  locations:
  - id: GO:0005886
    label: plasma membrane
- description: 'Core physiological function - by providing cysteine for GSH synthesis,
    xCT enables GPX4 to detoxify lipid peroxides and suppress ferroptosis.

    '
  molecular_function:
    id: GO:0015327
    label: cystine:glutamate antiporter activity
  directly_involved_in:
  - id: GO:0110076
    label: negative regulation of ferroptosis
  locations:
  - id: GO:0005886
    label: plasma membrane
- description: 'Novel function discovered in PMID:40280132 - SLC7A11 acts as an unconventional
    proton channel at lysosomal membranes, contributing to lysosomal pH regulation.

    '
  molecular_function:
    id: GO:0015252
    label: proton channel activity
  directly_involved_in:
  - id: GO:0035752
    label: lysosomal lumen pH elevation
  - id: GO:1902600
    label: proton transmembrane transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
proposed_new_terms: []
suggested_questions:
- question: 'What is the physiological significance of the newly discovered lysosomal
    proton channel activity of SLC7A11? How does this relate to ferroptosis regulation?

    '
- question: 'Does SLC7A11-mediated kynurenine transport (PMID:35245456) represent
    a major physiological substrate or is it primarily relevant in specific disease
    contexts?

    '
suggested_experiments:
- description: 'Comparative analysis of SLC7A11 proton channel vs antiporter activity
    under different cellular conditions (normal vs stress, plasma membrane vs lysosome)
    to understand the relative contributions of the two distinct activities.

    '
- description: 'Structure-function studies to identify residues that separate proton
    channel from antiporter activity, which could enable selective modulation of one
    activity without affecting the other.

    '
tags:
- ferroptosis

SLC7A11

Gene Description

Existing Annotations Review

Core Functions

Core physiological function - by providing cysteine for GSH synthesis, xCT enables GPX4 to detoxify lipid peroxides and suppress ferroptosis.

Novel function discovered in PMID:40280132 - SLC7A11 acts as an unconventional proton channel at lysosomal membranes, contributing to lysosomal pH regulation.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

📄 View Raw YAML