positive regulation of autophagosome maturation

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of autophagosome maturation. [GOC:autophagy, GOC:TermGenie, PMID:10436019, PMID:21383079]

Positive regulation of autophagosome maturation is a complex process essential for the efficient degradation of cellular components via autophagy. It involves a series of tightly regulated steps that ensure the proper formation and maturation of autophagosomes, the double-membrane vesicles that encapsulate the cargo destined for lysosomal degradation.

1. **Initiation:** Autophagy is triggered by various cellular stresses, including nutrient deprivation, oxidative stress, and pathogen infection. This initiates the formation of phagophores, the precursor structures to autophagosomes. The key player in this stage is the ULK1 complex, which consists of ULK1, ATG13, FIP200, and ATG101. This complex is activated by the inactivation of mTORC1, a negative regulator of autophagy, in response to stress signals.

2. **Nucleation and Elongation:** Once activated, the ULK1 complex recruits and activates other autophagy-related proteins, such as the ATG9 complex and the PI3KC3 complex. The ATG9 complex, containing ATG9, ATG2, and ATG18, is involved in the delivery of lipids to the growing phagophore membrane. The PI3KC3 complex, consisting of VPS34, Beclin-1, ATG14, and VPS15, generates phosphatidylinositol 3-phosphate (PI3P) on the phagophore membrane, which acts as a docking site for other autophagy proteins.

3. **Closure and Maturation:** The phagophore continues to expand and engulf the cellular cargo. Once it has enclosed the cargo, it closes into a double-membrane vesicle known as an autophagosome. This process is facilitated by the ATG5-ATG12-ATG16L1 complex, which acts as a scaffold for the recruitment and activation of ATG8/LC3. ATG8/LC3 is a ubiquitin-like protein that is conjugated to the autophagosome membrane. This conjugation is critical for the maturation and fusion of the autophagosome with lysosomes.

4. **Fusion with Lysosomes:** The mature autophagosome then travels through the cytoplasm and eventually encounters and fuses with lysosomes. This fusion event is mediated by the SNARE complex, which involves several proteins including STX17, SNAP29, and VAMP8. Once fused, the autophagosome content is degraded by the lysosomal hydrolases, releasing the breakdown products back into the cytoplasm for reuse.

In addition to these core steps, several other proteins and pathways regulate the efficiency and specificity of autophagosome maturation. These include:

* **Ubiquitin-mediated targeting:** Ubiquitinated proteins can be recognized and targeted for autophagic degradation through interactions with autophagy receptors like p62/SQSTM1 and NBR1.
* **Selective autophagy:** Different types of cargo can be specifically targeted for degradation through the recruitment of specific autophagy receptors. For example, mitophagy, the selective degradation of mitochondria, involves receptors like PINK1 and Parkin.
* **Chaperone-mediated autophagy:** Certain proteins are delivered to lysosomes directly through the action of chaperone proteins like Hsc70 and LAMP2A.

Dysregulation of autophagosome maturation can lead to a variety of diseases, including neurodegenerative diseases, cancer, and infectious diseases. Thus, understanding the molecular mechanisms underlying this process is essential for developing therapeutic strategies for these disorders.'
"

Proteins (3)

Compounds (132)