module: dmel_autophagosome_biogenesis
title: Autophagosome biogenesis by the core Atg machinery in Drosophila melanogaster
label: Autophagosome biogenesis
module_type: BIOLOGICAL_PROCESS
description: >-
  Macroautophagy begins with formation of a cup-shaped phagophore that expands
  and closes to form the double-membrane autophagosome. The core Atg proteins
  act in conserved functional units. The Atg1 kinase complex (Atg1, Atg13,
  Atg17/FIP200 and Atg101) initiates phagophore formation in response to
  nutrient starvation and TOR inhibition. The class III phosphatidylinositol
  3-kinase complex (Vps34/Pi3K59F, Vps15, Atg6/Beclin 1 and Atg14) produces
  phosphatidylinositol 3-phosphate at the phagophore. Atg9 vesicles supply
  membrane and Atg9 has phospholipid scramblase activity, while Atg2, recruited
  with the PI3P-binding Atg18 proteins, transfers lipids to the expanding
  phagophore. Two ubiquitin-like conjugation systems act downstream: Atg7 and
  Atg10 conjugate Atg12 to Atg5, and the Atg12-Atg5-Atg16 complex promotes
  lipidation of Atg8 proteins with phosphatidylethanolamine by Atg7 and Atg3
  after processing of Atg8 by the Atg4 proteases. In Drosophila, the fat body
  of starved larvae is the classic setting for studying this pathway.
summary: >-
  Core Atg kinase, lipid kinase, lipid transfer and ubiquitin-like conjugation
  units that build the autophagosome.
concepts:
  - {id: GO:0000045, label: autophagosome assembly}
cellular_components:
  - {id: GO:0000407, label: phagophore assembly site}
notes: >-
  Boundary. The module contains the FlyBase core Atg genes and the Atg
  complexes. Pi3K59F and Vps15 enter through the FlyBase autophagy-specific PI3
  kinase complex group; they also act in endosomal PI3K complexes. Atg7 is
  placed in both conjugation systems because it is the E1 enzyme for both
  Atg12 and Atg8. Autophagosome-lysosome fusion (HOPS, SNAREs), cargo receptors
  and upstream TOR signalling are outside the module. The connections give the
  conventional order of action; parts also act partly in parallel.
parts:
  - id: atg1_kinase_complex
    label: Atg1 kinase complex
    role: initiation kinase complex
    group: ATG-PK
    complex: true
    complex_term: {id: GO:1990316, label: Atg1/ULK1 kinase complex}
    unit_functions:
      Atg1: {id: GO:0004674, label: protein serine/threonine kinase activity}
  - id: autophagy_pi3k_complex
    label: Autophagy-specific class III PI3K complex
    role: PI3P production at the phagophore
    group: ATG-PI3K
    complex: true
    complex_term: {id: GO:0035032, label: "phosphatidylinositol 3-kinase complex, class III"}
    unit_functions:
      Pi3K59F: {id: GO:0016303, label: 1-phosphatidylinositol-3-kinase activity}
  - id: atg9_vesicles
    label: Atg9
    role: membrane source and lipid scrambling
    genes: [Atg9]
    function: {id: GO:0017128, label: phospholipid scramblase activity}
  - id: atg2_atg18_lipid_transfer
    label: Atg2-Atg18 lipid transfer unit
    role: lipid transfer to the phagophore
    genes: [Atg2, Atg18a, Atg18b]
    unit_functions:
      Atg2: {id: GO:0120013, label: lipid transfer activity}
      Atg18a: {id: GO:0032266, label: phosphatidylinositol-3-phosphate binding}
      Atg18b: {id: GO:0032266, label: phosphatidylinositol-3-phosphate binding}
  - id: atg12_conjugation
    label: Atg12 conjugation system
    role: Atg12-Atg5 conjugation
    genes: [Atg7, Atg10, Atg12]
    unit_functions:
      Atg7: {id: GO:0019778, label: Atg12 activating enzyme activity}
      Atg10: {id: GO:0019777, label: Atg12 transferase activity}
  - id: atg12_atg5_atg16_complex
    label: Atg12-Atg5-Atg16 complex
    role: E3-like complex for Atg8 lipidation
    group: ATG-C
    complex: true
    complex_term: {id: GO:0034274, label: Atg12-Atg5-Atg16 complex}
  - id: atg8_lipidation
    label: Atg8 processing and lipidation system
    role: Atg8 processing and conjugation to phosphatidylethanolamine
    genes: [Atg4a, Atg4b, Atg7, Atg3, Atg8a, Atg8b]
    unit_functions:
      Atg4a: {id: GO:0004197, label: cysteine-type endopeptidase activity}
      Atg4b: {id: GO:0004197, label: cysteine-type endopeptidase activity}
      Atg7: {id: GO:0019779, label: Atg8 activating enzyme activity}
      Atg3: {id: GO:0019776, label: Atg8-family ligase activity}
connections:
  - {source: atg1_kinase_complex, target: autophagy_pi3k_complex, connection_type: PRECEDES, description: The Atg1 complex initiates phagophore formation and recruits the PI3K complex.}
  - {source: autophagy_pi3k_complex, target: atg2_atg18_lipid_transfer, connection_type: PRECEDES, description: PI3P made by the PI3K complex recruits Atg18 with Atg2.}
  - {source: atg9_vesicles, target: atg2_atg18_lipid_transfer, connection_type: PRECEDES, description: Atg9 vesicles seed the phagophore that Atg2 expands by lipid transfer.}
  - {source: atg12_conjugation, target: atg12_atg5_atg16_complex, connection_type: PROVIDES_INPUT_FOR, description: Atg7 and Atg10 form the Atg12-Atg5 conjugate that assembles with Atg16.}
  - {source: atg12_atg5_atg16_complex, target: atg8_lipidation, connection_type: POSITIVELY_REGULATES, description: The Atg12-Atg5-Atg16 complex promotes Atg3-mediated Atg8 lipidation.}