regulation of macroautophagy

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of macroautophagy. [GOC:krc]

Macroautophagy, also known simply as autophagy, is a fundamental cellular process involving the degradation and recycling of cellular components within lysosomes. It plays a crucial role in maintaining cellular homeostasis, responding to stress, and regulating development and aging. The regulation of this process is intricate and involves multiple signaling pathways, protein complexes, and regulatory mechanisms.

The initiation of autophagy is triggered by various cellular stresses, including nutrient deprivation, hypoxia, oxidative stress, and pathogen infection. These stressors activate signaling cascades that converge on the formation of a double-membrane vesicle known as the phagophore.

Key signaling pathways involved in autophagy regulation include:

* **mTOR pathway:** mTOR (mammalian target of rapamycin) is a serine/threonine kinase that acts as a central regulator of cell growth, proliferation, and autophagy. In nutrient-rich conditions, mTOR is activated and suppresses autophagy. Conversely, nutrient deprivation or stress inhibits mTOR activity, leading to autophagy induction.
* **AMPK pathway:** AMPK (AMP-activated protein kinase) is a sensor of cellular energy status. When energy levels are low, AMPK is activated and promotes autophagy by inhibiting mTOR and activating other autophagy-inducing pathways.
* **MAPK pathway:** MAPKs (mitogen-activated protein kinases) are involved in various cellular responses, including stress signaling. Some MAPKs, such as JNK (c-Jun N-terminal kinase) and p38, can promote autophagy under specific stress conditions.
* **ULK1 complex:** The ULK1 (Unc-51-like kinase 1) complex is a key regulator of autophagy initiation. This complex consists of ULK1, FIP200 (focal adhesion kinase family-interacting protein of 200 kDa), ATG13 (autophagy-related gene 13), and ATG101. Upon activation by upstream signaling pathways, ULK1 phosphorylates downstream proteins, including ATG13 and FIP200, to promote phagophore formation.

Once the phagophore is formed, it elongates and engulfs cellular components, including organelles, protein aggregates, and intracellular pathogens. This process is facilitated by the coordinated action of several autophagy-related (ATG) proteins.

* **ATG proteins:** A large number of ATG proteins are involved in various steps of autophagy, including phagophore formation, cargo selection, and fusion with lysosomes. These proteins interact with each other and with other cellular components to ensure efficient autophagic flux.
* **LC3 conjugation:** LC3 (microtubule-associated protein 1 light chain 3) is a ubiquitin-like protein that plays a crucial role in the expansion of the phagophore membrane. LC3 is conjugated to phosphatidylethanolamine (PE) on the phagophore membrane, a process known as LC3 lipidation. This conjugation is mediated by a series of ATG proteins and is essential for autophagosome formation.
* **Lysosome fusion:** Finally, the completed autophagosome fuses with lysosomes, which contain hydrolytic enzymes. The lysosomal enzymes degrade the engulfed cargo, generating building blocks that can be reused by the cell. This process, known as autophagic degradation, is essential for the recycling of cellular components and the maintenance of cellular homeostasis.

The regulation of autophagy is a highly dynamic process that involves multiple levels of control. Dysregulation of autophagy has been linked to various diseases, including cancer, neurodegenerative disorders, and infectious diseases. Therefore, understanding the complex mechanisms of autophagy regulation is crucial for developing therapeutic strategies targeting these diseases.'
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Proteins (20)

Compounds (636)