negative regulation of autophagosome maturation

Definition

Target type: biologicalprocess

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

Negative regulation of autophagosome maturation is a complex process that involves the suppression of the formation and/or development of autophagosomes, the double-membrane vesicles responsible for engulfing cellular components during autophagy. This process is crucial for maintaining cellular homeostasis and preventing excessive or inappropriate degradation of cellular components. Several key pathways and factors contribute to the negative regulation of autophagosome maturation:

1. **Inhibition of Autophagosome Formation:**
- **mTOR signaling:** The mammalian target of rapamycin (mTOR) is a key regulator of autophagy. When activated, mTOR phosphorylates and inhibits key autophagy proteins such as ULK1 and ATG13, preventing the formation of the phagophore, the initial membrane structure that gives rise to the autophagosome.
- **PI3K/Akt signaling:** The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is another important regulator of autophagy. Activation of this pathway can inhibit autophagy by promoting mTOR activity.
- **Negative feedback loops:** Several autophagy proteins themselves regulate their own activity through negative feedback loops. For example, ATG9A, a protein involved in phagophore formation, can negatively regulate its own activity through an unknown mechanism.

2. **Interference with Autophagosome Elongation and Closure:**
- **LC3 lipidation:** The lipidation of LC3, a protein essential for autophagosome formation, is tightly regulated. Inhibiting LC3 lipidation by interfering with the ATG4-ATG7-ATG3 complex can block autophagosome elongation.
- **p62/SQSTM1:** p62 is a cargo receptor that binds to ubiquitinated proteins and targets them for degradation by autophagy. However, p62 can also negatively regulate autophagosome formation by sequestering autophagy proteins like ATG5.

3. **Suppression of Autophagosome Maturation and Fusion with Lysosomes:**
- **SNARE proteins:** Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are critical for vesicle fusion. Inhibiting specific SNARE proteins involved in autophagosome-lysosome fusion can block the delivery of autophagic cargo for degradation.
- **Rab proteins:** Rab GTPases, such as Rab7, are involved in regulating vesicle trafficking and fusion. Inhibiting Rab7 activity can prevent autophagosome maturation and fusion with lysosomes.

4. **Regulation by Transcriptional Factors:**
- **Transcription factors:** Transcription factors such as FOXO3a and TFEB can promote autophagy by upregulating the expression of autophagy genes. Inhibition of these transcription factors can negatively regulate autophagosome maturation.

5. **Post-translational Modifications:**
- **Ubiquitination and phosphorylation:** Ubiquitination and phosphorylation of autophagy proteins can regulate their activity, stability, and localization, thereby influencing autophagosome maturation.

The precise mechanism of negative regulation of autophagosome maturation can vary depending on the specific cellular context and the initiating stress. This complex interplay of signaling pathways and protein interactions ensures that autophagy is tightly controlled and only activated when necessary.'"

Proteins (1)

Compounds (2)