regulation of chaperone-mediated autophagy

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of chaperone-mediated autophagy. [GO_REF:0000058, GOC:pad, GOC:PARL, GOC:TermGenie, PMID:20176123]

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that plays a crucial role in maintaining cellular homeostasis by removing damaged or misfolded proteins. The process is tightly regulated, ensuring that only specific target proteins are degraded. Here's a detailed breakdown of the key steps involved:

**1. Recognition and Targeting:**

* CMA begins with the recognition of target proteins by the cytosolic chaperone protein complex, **heat shock cognate 70 (HSC70)**. HSC70 binds to a specific amino acid motif, **KFERQ** (or similar variations), present on the target protein. This motif acts as a signal for CMA.
* Once bound, HSC70 interacts with the **lysosomal receptor protein, LAMP-2A**, which resides on the lysosomal membrane. LAMP-2A acts as a gateway for CMA substrates to enter the lysosome.

**2. Unfolding and Translocation:**

* The target protein, bound to HSC70, is transported to the lysosomal membrane.
* At the lysosome, the **lysosomal-associated protein type 2A (LAMP-2A)** receptor facilitates the unfolding of the target protein, making it suitable for entry into the lysosome.
* The unfolded protein then passes through a **translocation pore** formed by multiple LAMP-2A molecules, entering the lysosomal lumen.

**3. Degradation:**

* Inside the lysosome, the target protein encounters various **lysosomal hydrolases**, including proteases, lipases, and nucleases. These enzymes break down the protein into its constituent amino acids, completing the degradation process.

**4. Regulation of CMA:**

* **Regulation at the level of LAMP-2A:** LAMP-2A is essential for CMA, and its levels are tightly controlled.
* **Protein turnover:** LAMP-2A is constantly degraded and resynthesized, maintaining a dynamic equilibrium.
* **Phosphorylation:** Phosphorylation of LAMP-2A can affect its association with the lysosomal membrane, thereby influencing CMA activity.
* **Proteolytic cleavage:** LAMP-2A can be cleaved by proteases, reducing its availability for CMA.
* **Regulation at the level of HSC70:** The availability of HSC70 can also influence CMA.
* **Stress conditions:** Under cellular stress, HSC70 may be sequestered by other chaperones or involved in protein folding, limiting its availability for CMA.
* **Regulation at the level of the target protein:** The presence of the KFERQ motif and its accessibility to HSC70 are crucial for target protein recognition by CMA.

**5. Physiological Significance of CMA:**

* **Protein quality control:** CMA eliminates damaged or misfolded proteins, preventing the accumulation of harmful aggregates that can lead to cellular dysfunction.
* **Metabolic adaptation:** CMA contributes to cellular adaptation to changes in nutrient availability and energy demands.
* **Cellular stress response:** CMA is upregulated during stress conditions, such as starvation, to provide nutrients and protect against damage.
* **Disease relevance:** Dysregulation of CMA has been implicated in various diseases, including cancer, neurodegenerative disorders, and aging.

**CMA is a highly regulated process, and its fine-tuning ensures the selective degradation of target proteins while maintaining cellular integrity.**'
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Proteins (1)

Compounds (7)