module: dmel_rhg_apoptosome_caspase_activation
title: RHG proteins, Diap1 and the Dark apoptosome in Drosophila caspase activation
label: RHG-apoptosome caspase activation
module_type: BIOLOGICAL_PROCESS
description: >-
  In Drosophila cells, the initiator caspase Dronc is kept inactive by the
  inhibitor of apoptosis protein Diap1, an E3 ubiquitin ligase that binds and
  ubiquitylates Dronc and effector caspases. Apoptotic stimuli induce the RHG
  proteins Reaper (Rpr), Head involution defective (Hid), Grim and Sickle (Skl),
  which share an N-terminal IAP-binding motif. They bind Diap1, displace the
  caspases and promote Diap1 degradation. Freed Dronc is recruited by the adaptor
  Dark into the apoptosome, a wheel-shaped complex in which Dronc is activated and
  then cleaves the effector caspases drICE and Dcp-1. The mitochondrial serine
  protease HtrA2 (Omi) also binds IAPs and can promote cell death.
summary: >-
  RHG IAP antagonists release Dronc from Diap1 inhibition so that the Dark
  apoptosome can activate it.
concepts:
  - {id: GO:0006915, label: apoptotic process}
  - {id: GO:0043293, label: apoptosome}
parts:
  - id: rhg_iap_antagonists
    label: RHG IAP antagonists
    role: Diap1 antagonists
    genes: [rpr, hid, grim, skl]
    complex: false
    processes:
      - {id: GO:0043065, label: positive regulation of apoptotic process}
  - id: other_rhg_group_members
    label: Other FlyBase RHG group members
    role: other IAP-binding proteins
    description: >-
      HtrA2, a mitochondrial serine protease with an IAP-binding motif, and Prx4,
      which FlyBase includes in the RHG group.
    genes: [HtrA2, Prx4]
    complex: false
  - id: diap1
    label: Diap1
    role: caspase inhibitor and E3 ubiquitin ligase
    genes: [Diap1]
    function: {id: GO:0061630, label: ubiquitin protein ligase activity}
  - id: dark_apoptosome
    label: Dark-Dronc apoptosome
    role: initiator caspase activation platform
    group: APOP
    complex: true
    complex_term: {id: GO:0043293, label: apoptosome}
    unit_functions:
      Dark: {id: GO:0008656, label: cysteine-type endopeptidase activator activity involved in apoptotic process}
      Dronc: {id: GO:0004197, label: cysteine-type endopeptidase activity}
connections:
  - source: rhg_iap_antagonists
    target: diap1
    connection_type: NEGATIVELY_REGULATES
    description: >-
      RHG proteins bind the BIR domains of Diap1, displace bound caspases and promote
      Diap1 degradation.
  - source: diap1
    target: dark_apoptosome
    connection_type: NEGATIVELY_REGULATES
    description: Diap1 binds and ubiquitylates Dronc, keeping it inactive.
notes: >-
  Diap1 is not a member of the FlyBase APOP or RHG groups; it is added as a
  non-member gene because the RHG proteins act by antagonizing it. Effector caspases
  (Drice, Dcp-1) are downstream and are covered by apoptosis execution modules, not
  this one. Prx4 is kept because FlyBase places it in the RHG group, but its role as
  an IAP antagonist is not described here and should be checked. The upstream
  transcriptional induction of rpr, hid and grim (for example by p53 or ecdysone)
  is context.
groups: [APOP, RHG]