GO:0090117 endosome to lysosome transport of low-density lipoprotein particle: Cholesterol Clearance Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0090117 describes the directed movement of low-density lipoprotein (LDL) particles from endosomes to lysosomes, a key step in cellular cholesterol handling [1,4].
• This process is essential for delivering LDL-derived cholesterol to lysosomes for hydrolysis and subsequent cellular distribution.
• Defects in endosome-to-lysosome LDL transport contribute to foam cell formation and atherosclerosis [1,4].
• Key proteins include LDLR, LRP1, sortilin, Lamp1, and NPC1, which mediate uptake, sorting, and lysosomal delivery [2,5,6].
• Experimental models such as CRISPR knockout and knock-in cell lines enable precise dissection of this pathway [2,5].
• Understanding this process informs therapeutic strategies for cardiovascular disease and lysosomal storage disorders [3,6].
Description
Low-density lipoprotein (LDL) particles are the primary carriers of cholesterol in the bloodstream, and their efficient clearance by cells is critical for lipid homeostasis [1,4]. After binding to cell-surface receptors such as the LDL receptor (LDLR), LDL is internalized into endosomes and must then be transported to lysosomes for degradation and release of free cholesterol. This directed movement is formally described by the Gene Ontology term GO:0090117, endosome to lysosome transport of low-density lipoprotein particle [1,4]. Researchers study this process to understand how cells manage cholesterol and how its dysregulation leads to diseases like atherosclerosis [1,4]. The pathway involves a series of vesicular trafficking events and protein interactions that ensure LDL is delivered to the lysosomal lumen. Defects in this transport can cause cholesterol accumulation, foam cell formation, and inflammation [1,4]. Thus, GO:0090117 represents a focal point for investigating lipid metabolism and related pathologies [3,6].
endosome to lysosome transport of low-density lipoprotein particle At A Glance
| GO ID | GO:0090117 |
|---|---|
| GO term | endosome to lysosome transport of low-density lipoprotein particle |
| Ontology | biological_process |
| Synonym | endosome to lysosome transport of LDL |
| Major function | Delivery of LDL particles from endosomes to lysosomes for cholesterol hydrolysis and cellular utilization |
| Related cellular components | Endosome, lysosome, multivesicular body |
| Key molecular players | LDLR, LRP1, sortilin, Lamp1, NPC1 |
| Associated diseases | Atherosclerosis, lysosomal storage disorders, cardiovascular disease |
What Is GO:0090117?
GO:0090117 is defined as the directed movement of low-density lipoprotein particles from endosomes to lysosomes [1,4]. In other words, it is the cellular process that carries internalized LDL from the endosomal compartment to the lysosome for degradation and cholesterol release.
Why Is endosome to lysosome transport of low-density lipoprotein particle Important in Cell Biology?
This process is central to cholesterol homeostasis because it determines how much LDL-derived cholesterol reaches the lysosome for regulatory and biosynthetic purposes [1,4]. When endosome-to-lysosome LDL transport is impaired, cholesterol accumulates in macrophages, promoting foam cell formation and atherosclerosis [1,4]. Moreover, proper lysosomal delivery is required for the function of lysosomal acid lipase, which hydrolyzes cholesteryl esters. Studying GO:0090117 helps identify therapeutic targets for cardiovascular disease and lipid disorders [3,6].
• Maintains cellular cholesterol balance by delivering LDL to lysosomes for hydrolysis [1,4].
• Prevents cholesterol accumulation and foam cell formation in macrophages [1,4].
• Supports lysosomal function and acid lipase activity.
• Implicated in atherosclerosis and cardiovascular disease [1,4].
• Relevant to lysosomal storage disorders such as Niemann-Pick type C.
• Provides targets for lipid-lowering therapies [3,6].
• Involves endosomal sorting machinery that can be studied with CRISPR screens [2,5].
• Links to autophagy and membrane trafficking pathways.
• Affects inflammatory signaling in macrophages.
• Can be modeled in Drosophila and mammalian cells for genetic studies.
What Happens During endosome to lysosome transport of low-density lipoprotein particle?
LDL uptake and endosome formation
In simple terms: Cells take in LDL particles from the outside, packaging them into small vesicles called endosomes.
LDL particles bind to cell-surface receptors such as LDLR and LRP1, triggering internalization into clathrin-coated pits [1,4,5]. These vesicles mature into early endosomes, where the LDL particles remain intact. The endosomal lumen becomes acidified, which can cause dissociation of LDL from its receptor.
Sorting and vesicle trafficking
In simple terms: Inside the cell, LDL-containing endosomes are sorted and moved toward lysosomes.
Sortilin and other sorting receptors facilitate the packaging of LDL into transport vesicles destined for lysosomes. Membrane contact sites between endosomes and other organelles, including lysosomes, are important for cholesterol transfer and vesicle formation. The small GTPases and SNARE proteins mediate the docking and fusion of these vesicles with lysosomes.
Lysosomal delivery and hydrolysis
In simple terms: Once LDL reaches the lysosome, it is broken down to release cholesterol.
LDL particles are delivered to lysosomes where lysosomal acid lipase hydrolyzes cholesteryl esters into free cholesterol and fatty acids. Lamp1, a lysosomal membrane protein, is involved in lipid transport and lysosomal function, although its role may be partially dispensable in some contexts. The released cholesterol is then exported from the lysosome by NPC1 and NPC2 proteins.
Regulation and feedback
In simple terms: The cell monitors cholesterol levels and adjusts LDL transport accordingly.
Cholesterol levels regulate the expression of LDLR and other genes through SREBP transcription factors [1,4]. Sortilin levels can modulate the efficiency of endosome-to-lysosome LDL transport. Sphingosine 1-phosphate receptor 1 signaling in macrophages can influence atherosclerosis by affecting lipid handling.
Key Genes Involved in GO:0090117 endosome to lysosome transport of low-density lipoprotein particle
The following genes and proteins are experimentally implicated in endosome to lysosome transport of low-density lipoprotein particles.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LDLR | Binds and internalizes LDL particles | Mutations cause familial hypercholesterolemia; target for CRISPR KO [1,4] |
| LRP1 | Receptor for multiple ligands including LDL; mediates uptake | Identified as CXCL14 receptor; involved in lipid metabolism |
| SORT1 | Sorting receptor that directs LDL to lysosomes | Regulates LDL transport; linked to cardiovascular disease |
| LAMP1 | Lysosomal membrane protein; involved in lipid transport | Mediates lipid transport but dispensable for autophagy in Drosophila |
| NPC1 | Lysosomal cholesterol exporter | Mutations cause Niemann-Pick type C; key for cholesterol egress |
| NPC2 | Lysosomal cholesterol transfer protein | Works with NPC1 to export cholesterol |
| APOE | Lipoprotein component; affects LDL clearance | Isoforms influence atherosclerosis risk [1,4] |
| APOB | Structural protein of LDL | Required for LDL particle formation and receptor binding [1,4] |
| PCSK9 | Promotes LDLR degradation | Target of lipid-lowering drugs; CRISPR KO models available [1,4] |
| IDOL | E3 ubiquitin ligase that degrades LDLR | Regulates LDLR levels; potential therapeutic target [1,4] |
| MTOR | Kinase that regulates autophagy and lysosomal function | Modulates endosome-lysosome trafficking |
| RAB7 | Late endosomal GTPase | Required for endosome-lysosome fusion |
| SNARE proteins | Mediate vesicle fusion | Essential for lysosomal delivery |
| S1PR1 | Sphingosine 1-phosphate receptor | Signaling reduces atherosclerosis in LDLR-deficient mice |
| CXCL14 | Chemokine that binds LRP1 | Identified as LRP1 ligand; may affect lipid transport |
| LIPA | Lysosomal acid lipase | Hydrolyzes cholesteryl esters; mutations cause CESD |
| SCARB1 | Scavenger receptor BI | Mediates HDL cholesterol uptake; affects atherosclerosis [1,4] |
| ABCA1 | Cholesterol efflux pump | Mutations cause Tangier disease; relevant to foam cells [1,4] |
How Is endosome to lysosome transport of low-density lipoprotein particle Regulated?
The endosome to lysosome transport of LDL is regulated at multiple levels. Cholesterol availability controls the expression of LDLR and other genes via the SREBP pathway [1,4]. Sortilin levels modulate the sorting of LDL into lysosomal transport vesicles. Sphingosine 1-phosphate receptor 1 signaling in macrophages can reduce atherosclerosis by influencing lipid handling. Additionally, mTOR signaling affects lysosomal function and autophagy, which intersect with LDL trafficking.
endosome to lysosome transport of low-density lipoprotein particle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LDLR | Familial hypercholesterolemia; atherosclerosis | CRISPR KO in HepG2 or iPSC-derived hepatocytes |
| NPC1 | Niemann-Pick type C; lysosomal cholesterol storage | Knock-in of patient mutations in HeLa or neuronal cells |
| SORT1 | Cardiovascular disease; altered LDL transport | Overexpression and KO in macrophage cell lines |
| LRP1 | Atherosclerosis; lipid metabolism | KO in macrophages or smooth muscle cells |
| LAMP1 | Lysosomal function; lipid transport | KO in Drosophila or mammalian cells |
Atherosclerosis and foam cell formation
Impaired endosome-to-lysosome LDL transport leads to cholesterol accumulation in macrophages, promoting foam cell formation and atherosclerosis [1,4]. S1PR1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice, highlighting the therapeutic potential of modulating this pathway.
Lysosomal storage disorders
Defects in lysosomal cholesterol export, such as in Niemann-Pick type C caused by NPC1 mutations, impair LDL-derived cholesterol utilization and lead to lysosomal storage. Sortilin has been implicated in lipid metabolism and may influence lysosomal disorders.
Cardiovascular disease and hypercholesterolemia
Mutations in LDLR cause familial hypercholesterolemia, characterized by defective LDL clearance and elevated plasma cholesterol [1,4]. LRP1 and sortilin also contribute to cardiovascular risk through their roles in lipoprotein metabolism [5,6].
From endosome to lysosome transport of low-density lipoprotein particle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate endosome-to-lysosome LDL transport? | CRISPR knockout in HeLa or macrophage cells |
| How does a disease-associated point mutation affect LDL trafficking? | Point mutation knock-in using CRISPR |
| Where does a protein localize during LDL transport? | Tagged knock-in with fluorescent protein |
| Does overexpression of gene Y enhance LDL clearance? | CRISPR activation or cDNA overexpression |
| Which genes are essential for lysosomal LDL delivery? | Genome-wide CRISPR library screening |
| How does a drug affect LDL transport? | Pharmacological perturbation in KO and wild-type cells |
How to Study the endosome to lysosome transport of low-density lipoprotein particle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Fluorescence microscopy | LDL particle movement and colocalization | Tracking endosome-to-lysosome transport |
| CRISPR knockout screening | Gene essentiality for LDL transport | Identifying novel regulators [2,5] |
| Proteomics | Protein interactions and complexes | Discovering new components |
| Lipidomics | Cholesterol and cholesteryl ester levels | Quantifying pathway flux [1,4] |
| RNA-seq | Transcriptional changes | Assessing SREBP target gene expression [1,4] |
| Western blot | Protein expression and processing | Validating CRISPR KO efficiency |
| Flow cytometry | LDL uptake and cellular cholesterol | High-throughput screening |
| Immunofluorescence | Protein localization | Confirming lysosomal delivery |
Fluorescence microscopy
Two-color fluorescence microscopy can track LDL particles from endosomes to lysosomes in live cells. This method visualizes the transport process and can be combined with CRISPR knockouts to identify required genes.
CRISPR screening
Genome-wide CRISPR knockout screens can identify genes essential for endosome-to-lysosome LDL transport [2,5]. For example, screens in Drosophila cells have revealed roles for Lamp1 in lipid transport.
Proteomics and interactomics
Affinity purification coupled with mass spectrometry can identify protein complexes involved in LDL trafficking. Chemically synthesized probes have been used to identify LRP1 as a receptor for CXCL14, illustrating the power of chemical biology.
Lipidomics and cholesterol quantification
Mass spectrometry-based lipidomics measures cholesterol and cholesteryl ester levels to assess flux through the endosome-to-lysosome pathway [1,4]. This is often combined with genetic perturbations [1,4].
How CRISPR Can Be Used to Study GO:0090117 endosome to lysosome transport of low-density lipoprotein particle
Knockout
CRISPR knockout of genes such as LDLR, SORT1, or LAMP1 can reveal their requirement for endosome-to-lysosome LDL transport [2,6]. Knockout cell lines are valuable for dissecting the pathway and for drug screening.
Point Mutation
Introducing disease-associated point mutations (e.g., in NPC1 or LDLR) via CRISPR allows study of their impact on LDL trafficking and cholesterol homeostasis. This approach models familial hypercholesterolemia and lysosomal storage disorders.
Knock-in
Tagged knock-in of proteins like Lamp1 or LRP1 with fluorescent or affinity tags enables real-time imaging and proteomic analysis of LDL transport [5,8]. Knock-in of reporter genes can also monitor pathway activity.
Overexpression
CRISPR activation or cDNA overexpression of genes such as SORT1 or LRP1 can enhance LDL transport and clearance, providing gain-of-function models [5,6]. Overexpression studies help identify rate-limiting steps.
How EDITGENE Supports endosome to lysosome transport of low-density lipoprotein particle Research
Researchers studying endosome to lysosome transport of low-density lipoprotein particle-related genes often need to determine whether a candidate gene is causally involved in the pathway or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR services to enable such functional studies with high precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for endosome to lysosome transport of low-density lipoprotein particle research.
Frequently Asked Questions About endosome to lysosome transport of low-density lipoprotein particle
What is GO:0090117?
GO:0090117 is the Gene Ontology term for the directed movement of low-density lipoprotein particles from endosomes to lysosomes [1,4].
What genes are involved in endosome to lysosome transport of LDL?
Key genes include LDLR, LRP1, SORT1, LAMP1, NPC1, and NPC2, among others [1,4,5,6].
Why is endosome to lysosome LDL transport important?
It is essential for cholesterol homeostasis and prevents foam cell formation and atherosclerosis [1,4].
What diseases are linked to defective LDL transport?
Atherosclerosis, familial hypercholesterolemia, and Niemann-Pick type C are associated with defects in this pathway [1,4,6].
How can I study endosome to lysosome LDL transport?
Fluorescence microscopy, CRISPR screening, proteomics, and lipidomics are common methods [2,5,8].
What is the role of sortilin in LDL transport?
Sortilin sorts LDL into vesicles destined for lysosomes and regulates lipid metabolism.
Does Lamp1 play a role in LDL transport?
Lamp1 mediates lipid transport but is dispensable for autophagy in Drosophila, suggesting context-dependent functions.
What is the role of LRP1 in LDL transport?
LRP1 is a receptor that mediates the uptake of multiple ligands, including LDL, and is involved in lipid metabolism.
How does cholesterol regulate this pathway?
Cholesterol levels control SREBP-mediated expression of LDLR and other genes, providing feedback regulation [1,4].
Can CRISPR be used to study this pathway?
Yes, CRISPR knockout, knock-in, and overexpression models are powerful tools to dissect gene function in LDL transport [2,5,6].
Conclusion
GO:0090117, endosome to lysosome transport of low-density lipoprotein particle, is a fundamental biological process that ensures cellular cholesterol delivery and homeostasis [1,4]. Its dysregulation is intimately linked to atherosclerosis and lysosomal storage disorders, making it a prime target for therapeutic intervention [1,4,6]. Advances in CRISPR-based models and screening technologies continue to uncover new molecular players and regulatory mechanisms [2,5]. Researchers equipped with these tools can elucidate the precise steps of this pathway and translate findings into clinical applications [3,6].
References
- 1. Chistiakov DA et al.. 2017. Mechanisms of foam cell formation in atherosclerosis.. J Mol Med (Berl) 95(11):1153-1165 PMID: 28785870
- 2. Chaudhry N et al.. 2022. Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila.. Autophagy 18(10):2443-2458 PMID: 35266854
- 3. Potì F et al.. 2024. Sphingosine 1-phosphate receptor 1signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.. JCI Insight 9(24) PMID: 39531328
- 4. Chistiakov DA et al.. 2016. Macrophage-mediated cholesterol handling in atherosclerosis.. J Cell Mol Med 20(1):17-28 PMID: 26493158
- 5. Miyajima R et al.. 2024. Identification of Low-Density Lipoprotein Receptor-Related Protein 1 as a CXCL14 Receptor Using Chemically Synthesized Tetrafunctional Probes.. ACS Chem Biol 19(2):551-562 PMID: 38289037
- 6. Conlon DM. 2019. Role of sortilin in lipid metabolism.. Curr Opin Lipidol 30(3):198-204 PMID: 30946050
- 7. Ridgway ND et al.. 2018. Cholesterol transfer at endosomal-organelle membrane contact sites.. Curr Opin Lipidol 29(3):212-217 PMID: 29629999
- 8. Humphries WH 4th et al.. 2010. Intracellular degradation of low-density lipoprotein probed with two-color fluorescence microscopy.. Integr Biol (Camb) 2(10):536-44 PMID: 20852797
