module: dmel_imd_signaling
title: Imd signaling pathway in Drosophila melanogaster
label: Imd signaling
module_type: SIGNALING_PATHWAY
description: >-
  The immune deficiency (Imd) pathway is the main Drosophila defense against
  Gram-negative bacteria and some Gram-positive bacilli. It is triggered when
  DAP-type peptidoglycan binds the transmembrane receptor PGRP-LC or the
  intracellular receptor PGRP-LE. The receptors recruit the death-domain
  protein Imd, which assembles a complex with the adaptor Fadd and the caspase
  Dredd. Dredd cleaves Imd, and the E3 ligase Diap2, with the E2 enzymes Bendless
  and Effete and the E2 variant Uev1A, attaches K63-linked ubiquitin chains.
  These chains recruit the Tak1-Tab2 kinase complex, which activates the IKK
  complex (IKKbeta and Kenny). IKK phosphorylates the NF-kappa-B factor Relish,
  Dredd cleaves it, and the Rel homology domain enters the nucleus to induce
  antimicrobial peptide genes. Tak1 also activates the JNK branch (Hemipterous,
  Basket) that acts through AP-1 (Jra, Kayak).
summary: >-
  Peptidoglycan sensing by PGRP-LC/LE activates Imd, Fadd and Dredd, Tak1 and
  the IKK complex, leading to Relish-dependent antimicrobial peptide expression
  and a JNK/AP-1 branch.
concepts:
  - {id: GO:0061057, label: peptidoglycan recognition protein signaling pathway}
parts:
  - id: pgrp_receptors
    label: Peptidoglycan recognition receptors
    role: pattern recognition receptors
    genes: [PGRP-LC, PGRP-LE]
    complex: false
    function: {id: GO:0016019, label: peptidoglycan immune receptor activity}
  - id: imd_fadd_dredd
    label: Imd-Fadd-Dredd receptor-proximal complex
    role: death-domain adaptors and caspase
    genes: [imd, Fadd, Dredd]
    complex: false
    unit_functions:
      Dredd: {id: GO:0004197, label: cysteine-type endopeptidase activity}
  - id: imd_ubiquitination
    label: K63-linked ubiquitination machinery
    role: E3 ligase and E2 enzymes
    description: >-
      Diap2 is the E3 ligase; Bendless (Ubc13) with the non-catalytic variant
      Uev1A, and Effete, are the E2 enzymes.
    genes: [Diap2, ben, Uev1A, eff]
    complex: false
    unit_functions:
      Diap2: {id: GO:0061630, label: ubiquitin protein ligase activity}
      ben: {id: GO:0061631, label: ubiquitin conjugating enzyme activity}
      eff: {id: GO:0061631, label: ubiquitin conjugating enzyme activity}
  - id: tak1_tab2
    label: Tak1-Tab2 kinase complex
    role: MAP3 kinase
    genes: [Tak1, Tab2]
    complex: true
    unit_functions:
      Tak1: {id: GO:0004709, label: MAP kinase kinase kinase activity}
  - id: ikk_complex
    label: IKK complex
    role: IkappaB kinase complex
    genes: [IKKbeta, key]
    complex: true
    complex_term: {id: GO:0008385, label: IkappaB kinase complex}
    unit_functions:
      IKKbeta: {id: GO:0008384, label: IkappaB kinase activity}
  - id: relish
    label: Relish
    role: NF-kappa-B transcription factor output
    genes: [Rel]
    complex: false
    function: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
  - id: jnk_branch
    label: JNK branch
    role: JNK cascade and AP-1 output
    parts:
      - id: jnk_kinases
        label: Hemipterous-Basket kinases
        role: MAP2K and JNK
        genes: [hep, bsk]
        complex: false
        unit_functions:
          hep: {id: GO:0004708, label: MAP kinase kinase activity}
          bsk: {id: GO:0004705, label: JUN kinase activity}
      - id: ap1
        label: AP-1 (Jra-Kayak)
        role: transcription factor
        genes: [Jra, kay]
        complex: true
        complex_term: {id: GO:0035976, label: transcription factor AP-1 complex}
        function: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
    connections:
      - {source: jnk_kinases, target: ap1, connection_type: POSITIVELY_REGULATES,
         description: "Basket (JNK) phosphorylates and activates Jra."}
  - id: foxo
    label: FOXO
    role: transcription factor
    description: >-
      FOXO is listed by FlyBase as a core component; it can induce antimicrobial
      peptide genes, and its position relative to the canonical Imd cascade is
      not resolved.
    genes: [foxo]
    complex: false
connections:
  - {source: pgrp_receptors, target: imd_fadd_dredd, connection_type: POSITIVELY_REGULATES,
     description: "Peptidoglycan-bound PGRP-LC/LE recruit Imd, which assembles with Fadd and Dredd."}
  - {source: imd_fadd_dredd, target: imd_ubiquitination, connection_type: PROVIDES_INPUT_FOR,
     description: "Dredd-cleaved Imd is K63-ubiquitinated by Diap2 with its E2 enzymes."}
  - {source: imd_ubiquitination, target: tak1_tab2, connection_type: POSITIVELY_REGULATES,
     description: "K63-linked chains recruit and activate Tak1-Tab2."}
  - {source: tak1_tab2, target: ikk_complex, connection_type: POSITIVELY_REGULATES,
     description: "Tak1 activates the IKK complex."}
  - {source: ikk_complex, target: relish, connection_type: POSITIVELY_REGULATES,
     description: "IKKbeta phosphorylates Relish, which is then cleaved by Dredd and enters the nucleus."}
  - {source: tak1_tab2, target: jnk_branch, connection_type: POSITIVELY_REGULATES,
     description: "Tak1 also activates the Hemipterous-Basket JNK cascade."}
knowledge_gaps:
  - gap_statement: >-
      How FOXO is connected to the Imd cascade, and whether it acts in parallel
      to Relish or as part of the pathway, is not established.
    boundary: Transcriptional outputs of Imd signaling.
    gap_kind: [BIOLOGY]
notes: >-
  Boundary. Core components only (FlyBase IMD-C). IKKbeta and Relish are shared
  with cGAS-STING signaling, and the JNK cascade is shared with JNK signaling.
  Amidase PGRPs, Pirk, Caspar, deubiquitinases and other FlyBase regulators are
  not parts. Tak1-Tab2 is emitted as a complex without a GO complex term.