negative regulation of autophagy

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of autophagy. Autophagy is the process in which cells digest parts of their own cytoplasm. [GOC:dph, GOC:tb]

Negative regulation of autophagy is a crucial cellular process that fine-tunes the autophagic pathway, preventing excessive or inappropriate degradation of cellular components. This intricate regulatory network involves a diverse array of molecular players, including proteins, lipids, and metabolites, orchestrating a complex interplay of signaling pathways.

Several key mechanisms contribute to negative regulation of autophagy:

1. **Inhibition of Autophagosome Formation:**
- **mTORC1 Signaling:** The mammalian target of rapamycin complex 1 (mTORC1) acts as a central hub in nutrient sensing. Upon nutrient availability, mTORC1 activates downstream targets that inhibit autophagy initiation, such as ULK1, a crucial autophagy kinase.
- **VPS34 Complex Inhibition:** The class III phosphatidylinositol 3-kinase (PI3K), also known as VPS34, is essential for autophagosome formation. Certain negative regulators, like Rubicon and AMBRA1, can inhibit VPS34 activity, thereby suppressing autophagosome biogenesis.
- **Atg5-Atg12 Conjugation Inhibition:** The conjugation of Atg5 and Atg12 is a critical step in autophagosome elongation. Negative regulators, such as Atg16L1, can interfere with this process, preventing proper autophagosome formation.

2. **Suppression of Autophagosome-Lysosome Fusion:**
- **Negative Regulation of Rab7:** Rab7 is a small GTPase that facilitates the fusion of autophagosomes with lysosomes. Negative regulators, such as TBC1D5 and RILPL2, can inhibit Rab7 activity, preventing lysosomal degradation.
- **Disruption of SNARE Complex Formation:** SNARE proteins are crucial for membrane fusion. Negative regulators, such as syntaxin 17, can interfere with SNARE complex formation, blocking autophagosome-lysosome fusion.

3. **Control of Autophagy Cargo Recognition:**
- **Selective Autophagy Receptor Inhibition:** Specific autophagy receptors, such as p62/SQSTM1 and NBR1, bind to cargo proteins, targeting them for degradation. Negative regulators can interfere with the function of these receptors, preventing the selective elimination of specific targets.

4. **Feedback Regulation:**
- **Autophagic Degradation of Autophagy Regulators:** Some negative regulators, like p62/SQSTM1, themselves undergo autophagic degradation. This feedback loop ensures that the autophagy pathway is not permanently suppressed.

5. **Regulation by Cellular Stress:**
- **Stress-Induced Inhibition:** Certain stresses, like hypoxia and endoplasmic reticulum stress, can temporarily inhibit autophagy, possibly to prioritize other cellular survival pathways.

Overall, negative regulation of autophagy is a finely tuned process that ensures the appropriate activation and modulation of autophagy in response to diverse cellular stimuli. This intricate regulatory network safeguards cellular homeostasis and prevents the detrimental consequences of excessive or inappropriate autophagic degradation.'
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Proteins (20)

Compounds (675)