negative regulation of late endosome to lysosome transport

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of late endosome to lysosome transport. [GO_REF:0000058, GOC:pad, GOC:PARL, GOC:TermGenie, PMID:23949442]

Negative regulation of late endosome to lysosome transport is a complex process that involves the coordinated action of various proteins and cellular machinery. It plays a critical role in controlling the delivery of cargo from late endosomes to lysosomes, ensuring proper degradation of cellular components and maintaining cellular homeostasis.

Here's a detailed description of the process:

1. **Cargo Sorting and Packaging:** Late endosomes act as sorting stations for proteins and other macromolecules. They receive cargo from earlier compartments like early endosomes and Golgi. This cargo includes:
- **Proteins destined for degradation:** These are often misfolded proteins, signaling receptors that have been internalized, and other cellular components that need to be removed.
- **Transmembrane proteins:** Some transmembrane proteins are sorted to the plasma membrane, while others are directed to lysosomes for degradation.

2. **Rab GTPases and Tethering Factors:** Rab GTPases, small GTP-binding proteins, play crucial roles in vesicle trafficking. Specific Rab GTPases are associated with late endosomes and lysosomes, acting as molecular switches that regulate the recruitment of tethering factors. These tethering factors facilitate the initial docking of late endosome-derived vesicles with lysosomes.

3. **SNARE Proteins:** Once vesicles are tethered to the lysosomal membrane, SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) mediate the fusion of the vesicle membrane with the lysosomal membrane. This fusion event allows the delivery of cargo from the late endosome into the lysosomal lumen.

4. **Lysosomal Acidification and Proteases:** Lysosomes maintain an acidic pH environment, essential for the activity of lysosomal hydrolases. These hydrolases are a diverse group of enzymes that degrade a wide range of substrates, including proteins, lipids, carbohydrates, and nucleic acids.

5. **Negative Regulation Mechanisms:**
- **Protein Kinases and Phosphatases:** Phosphorylation and dephosphorylation events regulate the activity of proteins involved in late endosome to lysosome transport. For example, phosphorylation of Rab7, a Rab GTPase associated with late endosomes, can promote the fusion of late endosomes with lysosomes.
- **Ubiquitination:** Ubiquitination is a post-translational modification that plays a role in targeting proteins for degradation. Proteins destined for lysosomal degradation are often ubiquitinated, which serves as a signal for their sorting into late endosomes and subsequent delivery to lysosomes.
- **Signaling Pathways:** Various signaling pathways, such as the mTOR pathway and the MAPK pathway, can influence the activity of proteins involved in late endosome to lysosome transport.
- **Cellular Stress Responses:** Cells activate specific stress responses, such as autophagy, to cope with situations like nutrient deprivation or the accumulation of misfolded proteins. These stress responses can affect the transport of cargo from late endosomes to lysosomes.

6. **Lysosomal Degradation and Recycling:** Once inside the lysosome, the cargo is broken down into its constituent parts. The degradation products can then be recycled back into the cell or excreted.

7. **Role in Disease:** Dysregulation of late endosome to lysosome transport has been linked to various diseases, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease), lysosomal storage disorders, and cancer.

In summary, negative regulation of late endosome to lysosome transport is a highly regulated process that ensures the proper sorting, delivery, and degradation of cellular components. This process involves the coordinated action of a complex network of proteins and signaling pathways, which are intricately linked to maintaining cellular homeostasis and preventing disease.'
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Proteins (1)

Compounds (88)