ATG proteins

ATG proteins (short for “autophagy-related proteins”) are a group of conserved proteins essential for the process of autophagy, a cellular mechanism that degrades and recycles damaged organelles, misfolded proteins, and other cellular debris. They are named after the genes that encode them, discovered in yeast (Saccharomyces cerevisiae), and are found in most eukaryotic organisms.

Functions of ATG Proteins

ATG proteins orchestrate every step of autophagy, including:

  1. Initiation:
    • ATG proteins participate in signaling pathways that initiate autophagy in response to cellular stress, such as nutrient deprivation or damage.
    • Example: ULK1/ATG1 complex initiates autophagosome formation.
  2. Phagophore Formation:
    • ATG proteins are involved in the nucleation and expansion of the phagophore, the initial structure that will develop into the autophagosome.
    • Example: The Beclin-1/ATG6 complex recruits lipids and proteins to the forming membrane.
  3. Cargo Selection:
    • Some ATG proteins facilitate the recognition and selection of specific cellular materials for degradation.
    • Example: p62/SQSTM1 binds to ubiquitinated proteins and interacts with LC3/ATG8 to target them to the autophagosome.
  4. Autophagosome Formation:
    • ATG proteins mediate the expansion and closure of the phagophore to form the complete autophagosome.
    • Example: LC3/ATG8 is critical for membrane elongation and cargo attachment.
  5. Fusion with Lysosomes:
    • After the autophagosome forms, ATG proteins regulate its fusion with lysosomes, where the contents are degraded.
    • Example: ATG14 coordinates autophagosome-lysosome fusion.
  6. Recycling:
    • ATG proteins help recover basic building blocks (e.g., amino acids, fatty acids) after degradation, allowing cells to reuse them.

Key ATG Protein Complexes and Their Roles

  1. ULK1/ATG1 Complex:
    • Initiates autophagy by responding to upstream signals (e.g., low energy via AMPK or nutrient availability via mTORC1).
  2. Beclin-1/ATG6 Complex:
    • Recruits phosphatidylinositol 3-kinase (PI3K) activity for the nucleation of the phagophore membrane.
  3. ATG12–ATG5–ATG16L1 Complex:
    • Facilitates the lipidation of LC3/ATG8, which is critical for autophagosome membrane elongation.
  4. LC3/ATG8:
    • An essential marker of autophagosomes.
    • Involved in membrane expansion and cargo selection.
  5. ATG9:
    • Supplies lipids to the growing autophagosome membrane.

Regulation of ATG Proteins

  1. Nutrient Availability:
    • mTORC1 inhibits ATG proteins under nutrient-rich conditions.
    • AMPK activates ATG proteins during low energy states.
  2. Post-Translational Modifications:
    • ATG proteins can be regulated by phosphorylation, ubiquitination, or acetylation to fine-tune autophagy activity.

Clinical Relevance of ATG Proteins

  1. Neurodegenerative Diseases:
    • Defects in ATG proteins can impair autophagy, leading to the accumulation of toxic proteins in diseases like Alzheimer’s and Parkinson’s.
  2. Cancer:
    • ATG proteins can promote survival of cancer cells by providing nutrients through autophagy under stress conditions (e.g., hypoxia, nutrient starvation).
  3. Infectious Diseases:
    • ATG proteins play a role in eliminating intracellular pathogens, contributing to the immune defense.
  4. Metabolic Disorders:
    • Dysregulated ATG protein activity is linked to obesity, type 2 diabetes, and other metabolic syndromes.

In summary, ATG proteins are central players in the autophagy process, coordinating the formation, maturation, and degradation of autophagosomes. Their proper function is critical for cellular homeostasis, and their dysregulation is associated with various diseases.