GO:0015811 L-cystine transport: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0015811 L-cystine transport describes the directed movement of L-cystine across membranes, primarily mediated by the cystine/glutamate antiporter system xc- (SLC7A11/SLC3A2).
• L-cystine import is the rate-limiting step for glutathione synthesis and cellular redox defense, linking this process to ferroptosis sensitivity.
• SLC7A11, the core transporter of L-cystine, is regulated by p53, AMPK signaling, and hypoxia, making it a key node in cancer metabolism.
• Defective L-cystine transport causes cystinosis, a lysosomal storage disorder with renal and ocular manifestations.
• Dysregulated cystine transport is implicated in schizophrenia, glioblastoma, colorectal cancer, and other malignancies.
• CRISPR knockout, point mutation, and overexpression models of SLC7A11 and related genes are essential for dissecting L-cystine transport biology.
Description
L-cystine transport (GO:0015811) is the biological process by which the amino acid L-cystine is moved into, out of, or within cells via transporters or pores. This process is fundamental to cellular redox homeostasis because intracellular L-cystine is rapidly reduced to cysteine, the rate-limiting substrate for glutathione (GSH) synthesis. The cystine/glutamate antiporter system xc-, composed of SLC7A11 and SLC3A2, is the principal mediator of L-cystine uptake in many cell types. Research on L-cystine transport has accelerated due to its central role in ferroptosis, a form of iron-dependent cell death triggered by GSH depletion and lipid peroxidation. In cancer, high SLC7A11 expression supports antioxidant capacity and confers resistance to ferroptosis, making it a therapeutic target. In contrast, impaired cystine transport underlies cystinosis, a lysosomal storage disease caused by mutations in CTNS, the cystine exporter. Additionally, altered cystine/glutamate exchange has been linked to schizophrenia pathophysiology. Understanding the molecular players, regulation, and disease relevance of L-cystine transport is therefore critical for both basic cell biology and translational medicine.
L-cystine transport At A Glance
| GO ID | GO:0015811 |
|---|---|
| GO term | L-cystine transport |
| Ontology | biological_process |
| Synonym | (none) |
| Major function | Directed movement of L-cystine across cellular membranes via transporters or pores |
| Key transporters | SLC7A11 (xCT), SLC3A2 (CD98hc), CTNS (cystinosin) |
| Associated diseases | Cystinosis, cancer (glioblastoma, colorectal), schizophrenia |
| Regulatory inputs | p53, AMPK, hypoxia, oxidative stress |
| Research methods | CRISPR KO/knock-in, metabolic assays, ferroptosis induction, transport assays |
What Is GO:0015811?
According to the Gene Ontology, GO:0015811 L-cystine transport is defined as the directed movement of L-cystine (also known as dicysteine) into, out of, or within a cell, or between cells, by means of some agent such as a transporter or pore. This process encompasses both plasma membrane import and intracellular compartmental transport, and it is distinct from the transport of other amino acids. The term is a biological process and does not have synonyms in the current QuickGO release.
Why Is L-cystine transport Important in Cell Biology?
L-cystine transport is a critical control point for cellular antioxidant defense and redox balance. By supplying cysteine for glutathione synthesis, it determines susceptibility to ferroptosis, a cell death modality with broad implications in cancer, neurodegeneration, and ischemia-reperfusion injury. The transporter SLC7A11 is frequently overexpressed in cancers, where it supports tumor growth and therapy resistance. Conversely, loss-of-function mutations in CTNS cause cystinosis, highlighting the importance of lysosomal cystine export. Furthermore, the cystine/glutamate antiporter modulates synaptic glutamate levels and has been implicated in schizophrenia. Thus, studying L-cystine transport bridges fundamental cell biology with multiple disease contexts.
• Controls glutathione synthesis and cellular redox homeostasis.
• Determines sensitivity to ferroptosis, a key tumor suppression mechanism.
• SLC7A11 overexpression promotes cancer cell survival and resistance to therapy.
• Defective lysosomal cystine export causes cystinosis.
• Altered cystine/glutamate exchange is linked to schizophrenia.
• Hypoxia-induced metabolic reprogramming relies on cystine uptake in colorectal cancer.
• Provides a target for metabolic vulnerabilities in glioblastoma and other tumors.
• Essential for understanding amino acid transport in renal physiology.
• Involved in pentose phosphate pathway dependency and disulfide stress.
• Serves as a paradigm for studying transporter regulation by kinases and stress signals.
What Happens During L-cystine transport?
Substrate recognition and binding
In simple terms: The transporter first grabs L-cystine from outside the cell.
L-cystine transport begins with the recognition of extracellular L-cystine by a specific transporter. The cystine/glutamate antiporter system xc- (SLC7A11/SLC3A2) binds L-cystine with high affinity and couples its uptake to the efflux of glutamate. This exchange is electroneutral and driven by the concentration gradient of glutamate. In the kidney, brush border membrane vesicles mediate L-cystine transport via distinct carriers.
Translocation across the membrane
In simple terms: The transporter flips the amino acid across the cell membrane.
Upon binding, SLC7A11 undergoes conformational changes that translocate L-cystine into the cytoplasm while exporting glutamate. This process is sodium-independent and relies on the cystine/glutamate antiporter activity. In lysosomes, cystinosin (CTNS) exports cystine generated from protein degradation, a process defective in cystinosis.
Intracellular reduction to cysteine
In simple terms: Once inside, cystine is quickly converted to cysteine, the building block for antioxidants.
Imported L-cystine is rapidly reduced to cysteine, which is the rate-limiting substrate for glutathione (GSH) synthesis. This reduction is essential for maintaining the cellular redox environment and protecting against oxidative stress. The availability of cysteine directly influences GSH levels and ferroptosis sensitivity.
Regulation by cellular stress and signaling
In simple terms: The cell adjusts cystine import based on stress and nutrient signals.
L-cystine transport is regulated at multiple levels. p53 can repress SLC7A11 expression, thereby reducing cystine uptake and promoting ferroptosis during tumor suppression. AMPKα1 phosphorylates ZDHHC8, leading to SLC7A11 palmitoylation and stabilization, which enhances cystine transport and ferroptosis resistance in glioblastoma. Hypoxia also reprograms cysteine metabolism, increasing cystine uptake to support tumorigenesis.
Role in ferroptosis and metabolic stress
In simple terms: When cystine import fails, cells become vulnerable to a type of iron-dependent death called ferroptosis.
Inhibition of L-cystine transport depletes GSH, leading to lipid peroxidation and ferroptosis. Cancer cells with high SLC7A11 activity are resistant to ferroptosis, but they become dependent on the pentose phosphate pathway to manage disulfide stress. This metabolic vulnerability can be targeted therapeutically.
Key Genes Involved in GO:0015811 L-cystine transport
The following genes encode transporters, regulators, and accessory proteins directly involved in L-cystine transport and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC7A11 | Light chain of cystine/glutamate antiporter xc-, mediates L-cystine uptake | Central to ferroptosis, cancer metabolism, and oxidative stress |
| SLC3A2 | Heavy chain of system xc-, stabilizes SLC7A11 at the membrane | Required for functional cystine transport; target for KO studies |
| CTNS | Lysosomal cystine exporter | Mutations cause cystinosis; model for lysosomal transport |
| TP53 | Represses SLC7A11 expression, promoting ferroptosis | Links tumor suppression to cystine transport |
| AMPKα1 (PRKAA1) | Phosphorylates ZDHHC8 to regulate SLC7A11 palmitoylation | Modulates ferroptosis resistance in glioblastoma |
| ZDHHC8 | Palmitoyltransferase that stabilizes SLC7A11 | Regulates cystine transport via post-translational modification |
| GCLC | Catalyzes first step of glutathione synthesis using cysteine | Downstream effector of cystine transport |
| GCLM | Modulatory subunit of glutamate-cysteine ligase | Influences GSH levels and ferroptosis sensitivity |
| GPX4 | Glutathione peroxidase that detoxifies lipid peroxides | Ferroptosis regulator downstream of cystine transport |
| SLC1A1 | Neuronal glutamate transporter | Modulates extracellular glutamate affecting cystine/glutamate exchange |
| SLC7A5 | L-type amino acid transporter | May contribute to cystine transport in some contexts |
| SLC3A1 | Heavy chain for cystine transport in kidney | Renal cystine reabsorption; mutations cause cystinuria |
| SLC7A9 | Light chain for cystine transport in kidney | Renal cystine reabsorption; mutations cause cystinuria |
| NFE2L2 (NRF2) | Transcription factor upregulating SLC7A11 | Oxidative stress response linked to cystine transport |
| ATF4 | Stress-induced transcription factor promoting SLC7A11 expression | Integrates amino acid stress with cystine uptake |
| HIF1A | Hypoxia-inducible factor regulating metabolic reprogramming | Indirectly promotes cystine transport in tumors |
| MTOR | Kinase regulating cell growth and metabolism | May influence cystine transport via downstream signaling |
| KEAP1 | Negative regulator of NRF2 | Mutations lead to SLC7A11 overexpression in cancer |
How Is L-cystine transport Regulated?
L-cystine transport is regulated at transcriptional, post-transcriptional, and post-translational levels. The tumor suppressor p53 represses SLC7A11 transcription, reducing cystine uptake and sensitizing cells to ferroptosis. The transcription factor NRF2 (encoded by NFE2L2) upregulates SLC7A11 in response to oxidative stress, and KEAP1 mutations lead to constitutive NRF2 activation and high SLC7A11 expression in cancers. Hypoxia-inducible factor 1-alpha (HIF1A) promotes metabolic reprogramming that includes increased cystine uptake in colorectal cancer. AMPKα1 phosphorylates ZDHHC8, which then palmitoylates SLC7A11, enhancing its stability and ferroptosis resistance in glioblastoma. Additionally, SLC7A11 is an unconventional H+ transporter in lysosomes, suggesting pH-dependent regulation. These layers of regulation allow cells to adjust cystine import according to nutrient availability, oxidative stress, and oncogenic signals.
L-cystine transport and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CTNS | Cystinosis | CTNS knockout cell lines and patient-derived fibroblasts |
| SLC7A11 | Cancer (glioblastoma, colorectal), ferroptosis resistance | SLC7A11 knockout and overexpression in cancer cell lines |
| SLC3A2 | Cancer, immune regulation | SLC3A2 knockout models to study system xc- function |
| TP53 | Tumor suppression via ferroptosis | p53 wild-type and mutant isogenic cell lines |
| AMPKα1 | Glioblastoma, metabolic stress | AMPKα1 knockout and phospho-mimetic knock-in |
Cystinosis
Cystinosis is an autosomal recessive lysosomal storage disorder caused by mutations in CTNS, which encodes the lysosomal cystine exporter cystinosin. Defective L-cystine transport out of lysosomes leads to cystine accumulation, forming crystals that damage multiple organs, particularly the kidneys and eyes. This disease highlights the essential role of L-cystine transport in lysosomal homeostasis.
Cancer and ferroptosis
Many cancers overexpress SLC7A11 to sustain high glutathione levels and evade ferroptosis. In glioblastoma, AMPKα1-mediated palmitoylation of SLC7A11 promotes ferroptosis resistance, supporting tumor growth. Colorectal cancer cells under hypoxia reprogram cysteine metabolism to enhance cystine uptake, contributing to tumorigenesis. Targeting L-cystine transport is therefore a promising therapeutic strategy to induce ferroptosis in cancer cells.
Schizophrenia
The cystine/glutamate antiporter system xc- regulates extracellular glutamate levels, which are critical for synaptic transmission. Dysregulation of this antiporter has been implicated in schizophrenia pathophysiology, and SLC7A11 has been proposed as a biomarker and potential therapeutic target.
Renal transport disorders
In the kidney, L-cystine transport across brush border membranes is essential for amino acid reabsorption. Defects in renal cystine transporters can lead to cystinuria, characterized by cystine stones, although the specific transporters involved include SLC3A1 and SLC7A9.
From L-cystine transport-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SLC7A11 loss sensitize cells to ferroptosis? | SLC7A11 knockout cell lines |
| How does AMPKα1 phosphorylation of ZDHHC8 affect SLC7A11 stability? | ZDHHC8 point mutation (phospho-deficient/mimetic) knock-in |
| What is the role of CTNS in lysosomal cystine export? | CTNS knockout and knock-in of patient mutations |
| Can SLC7A11 overexpression confer ferroptosis resistance? | SLC7A11 overexpression in cancer cell lines |
| How does hypoxia regulate cystine transport? | HIF1A knockout or knockdown under hypoxia |
| Does SLC7A11 palmitoylation affect its localization? | Tagged SLC7A11 knock-in for imaging |
How to Study the L-cystine transport Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radiolabeled cystine uptake | Transport rate and kinetics | Characterizing SLC7A11 activity |
| GSH/GSSG assay | Redox balance | Assessing downstream effects of cystine transport |
| Lipid peroxidation (C11-BODIPY) | Ferroptosis induction | Linking cystine transport to cell death |
| CRISPR knockout screening | Gene essentiality for transport | Identifying novel regulators |
| Western blot | Protein expression and modification | SLC7A11 palmitoylation and stability |
| Immunofluorescence | Subcellular localization | Lysosomal cystine export by CTNS |
| RNA-seq | Transcriptional changes | Hypoxia-induced metabolic reprogramming |
| Seahorse metabolic analysis | Metabolic flux | Pentose phosphate pathway dependency |
Transport assays
Radiolabeled L-cystine uptake assays in cell lines or membrane vesicles measure transport activity directly. These assays can be performed under varying conditions (pH, inhibitors) to characterize transporter kinetics.
Metabolic and redox profiling
Glutathione levels, cysteine/cystine ratios, and lipid peroxidation are measured to assess the impact of L-cystine transport on cellular redox state. Ferroptosis induction and rescue experiments link transport activity to cell death.
Genetic screens and CRISPR
CRISPR knockout screens identify genes required for L-cystine transport and ferroptosis resistance. Point mutations in SLC7A11 or regulators can be introduced to dissect specific residues.
Imaging and subcellular localization
Fluorescent tagging of SLC7A11 or CTNS allows visualization of transporter trafficking and lysosomal localization. Live-cell imaging can monitor cystine uptake using fluorescent probes.
How CRISPR Can Be Used to Study GO:0015811 L-cystine transport
Knockout
CRISPR knockout of SLC7A11 or CTNS is used to abolish L-cystine transport, leading to glutathione depletion and ferroptosis sensitization. These models are essential for validating the role of specific transporters in disease contexts such as cancer and cystinosis.
Point Mutation
Point mutations in SLC7A11 or its regulators (e.g., ZDHHC8 phosphorylation sites) can be introduced to study post-translational regulation and transport activity. Such models help dissect signaling pathways that control cystine uptake.
Knock-in
Knock-in of tagged SLC7A11 (e.g., HA or GFP) allows real-time tracking of transporter localization and dynamics. Knock-in of patient-derived CTNS mutations recapitulates cystinosis phenotypes in cell models.
Overexpression
Overexpression of SLC7A11 confers ferroptosis resistance and supports tumor growth in cancer models. This approach is used to study the sufficiency of cystine transport in promoting antioxidant capacity.
How EDITGENE Supports L-cystine transport Research
Researchers studying L-cystine transport-related genes often need to determine whether a candidate gene is causally involved in transport, redox regulation, or ferroptosis. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling functional validation of genes like SLC7A11, CTNS, and their regulators.
Contact EDITGENE today to design your custom CRISPR model for L-cystine transport research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC1A4 Knockout HEK293 Cell Line | EDJ-KQ2483 | Human | 6509 | Details Get a Quote |
| CTNS Knockout HEK293 Cell Line | EDJ-KQ3072 | Human | 1497 | Details Get a Quote |
| SLC3A1 Knockout HEK293 Cell Line | EDJ-KQ5765 | Human | 6519 | Details Get a Quote |
| SLC7A9 Knockout HEK293 Cell Line | EDJ-KQ7296 | Human | 11136 | Details Get a Quote |
| SLC7A13 Knockout HEK293 Cell Line | EDJ-KQ14499 | Human | 157724 | Details Get a Quote |
| SLC7A11 Knockout HEK293 Cell Line | EDJ-KQ17899 | Human | 23657 | Details Get a Quote |
| SLC7A11 Knockout HeLa Cell Line | EDJ-KQ18180 | Human | 23657 | Details Get a Quote |
| CTNS Knockout A-549 Cell Line | EDJ-KQ22974 | Human | 1497 | Details Get a Quote |
| SLC1A4 Knockout HCT 116 Cell Line | EDJ-KQ23060 | Human | 6509 | Details Get a Quote |
| SLC1A4 Knockout HeLa Cell Line | EDJ-KQ23061 | Human | 6509 | Details Get a Quote |
| SLC3A1 Knockout A-549 Cell Line | EDJ-KQ29180 | Human | 6519 | Details Get a Quote |
| SLC7A11 Knockout HCT 116 Cell Line | EDJ-KQ18896 | Human | 23657 | Details Get a Quote |
| SLC7A11 Knockout A-549 Cell Line | EDJ-KQ20237 | Human | 23657 | Details Get a Quote |
| SLC1A4 Knockout A-549 Cell Line | EDJ-KQ21699 | Human | 6509 | Details Get a Quote |
| CTNS Knockout HCT 116 Cell Line | EDJ-KQ24352 | Human | 1497 | Details Get a Quote |
Displaying Records 1 To 15 Of 24 Records
Frequently Asked Questions About L-cystine transport
What is L-cystine transport?
L-cystine transport (GO:0015811) is the directed movement of L-cystine across cellular membranes via transporters or pores, primarily mediated by the cystine/glutamate antiporter system xc-.
What genes are involved in L-cystine transport?
Key genes include SLC7A11, SLC3A2, CTNS, and regulators such as TP53, AMPKα1, and ZDHHC8.
How is L-cystine transport related to ferroptosis?
L-cystine import is required for glutathione synthesis; its inhibition depletes GSH and triggers ferroptosis, an iron-dependent cell death.
What diseases are associated with defective L-cystine transport?
Cystinosis, cancer (e.g., glioblastoma, colorectal), schizophrenia, and cystinuria are linked to altered L-cystine transport.
What is the role of SLC7A11 in cancer?
SLC7A11 is overexpressed in many cancers, supporting antioxidant defense and ferroptosis resistance, making it a therapeutic target.
How is L-cystine transport regulated?
It is regulated by p53, NRF2, HIF1A, AMPK signaling, and post-translational modifications like palmitoylation.
What methods are used to study L-cystine transport?
Radiolabeled uptake assays, glutathione measurements, CRISPR screens, and imaging are commonly used.
What is the difference between L-cystine and L-cysteine?
L-cystine is the oxidized dimer of cysteine; it is transported into cells and reduced to cysteine for glutathione synthesis.
Can CRISPR be used to study L-cystine transport?
Yes, CRISPR knockout, knock-in, and point mutation models are powerful tools to dissect transporter function and regulation.
What is cystinosis?
Cystinosis is a lysosomal storage disorder caused by CTNS mutations, leading to defective lysosomal cystine export and crystal accumulation.
Conclusion
L-cystine transport (GO:0015811) is a fundamental biological process that controls cellular redox balance, ferroptosis sensitivity, and amino acid homeostasis. Its dysregulation is implicated in a wide range of diseases, from cystinosis to cancer and schizophrenia. The central transporter SLC7A11 and its regulators are promising therapeutic targets, and ongoing research continues to uncover new layers of regulation. CRISPR-based models are indispensable for functionally validating these mechanisms and accelerating translational discoveries.
References
- 1. Zhou N et al.. 2025. SLC7A11 is an unconventional H(+) transporter in lysosomes.. Cell 188(13):3441-3458.e25 PMID: 40280132
- 2. Jiang L et al.. 2015. Ferroptosis as a p53-mediated activity during tumour suppression.. Nature 520(7545):57-62 PMID: 25799988
- 3. Gahl WA et al.. 2002. Cystinosis.. N Engl J Med 347(2):111-21 PMID: 12110740
- 4. Wang Z et al.. 2024. AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma.. Cancer Lett 584:216619 PMID: 38211651
- 5. Hung CC et al.. 2021. Cystine/Glutamate Antiporter in Schizophrenia: From Molecular Mechanism to Novel Biomarker and Treatment.. Int J Mol Sci 22(18) PMID: 34575878
- 6. Liu X et al.. 2020. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer.. Nat Cell Biol 22(4):476-486 PMID: 32231310
- 7. Lin Z et al.. 2024. Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer.. Redox Biol 75:103286 PMID: 39079386
- 8. Biber J et al.. 1983. Transport of L-cystine by rat renal brush border membrane vesicles.. Pflugers Arch 396(4):335-41 PMID: 6844138
