module: dmel_cgas_sting_signaling
title: cGAS-STING signaling pathway in Drosophila melanogaster
label: cGAS-STING signaling
module_type: SIGNALING_PATHWAY
description: >-
  Drosophila has two cGAS-like receptors, cGlr1 and cGlr2, that sense
  infection-associated nucleic acids and synthesize cyclic GMP-AMP
  dinucleotides. cGlr1 is activated by double-stranded RNA and produces
  3',2'-cGAMP. The cyclic dinucleotides bind Sting, which signals through the
  IKK kinases to activate the NF-kappa-B family transcription factor Relish.
  Relish then induces Sting-regulated genes that restrict RNA virus infection.
summary: >-
  cGAS-like receptors make cyclic GMP-AMP that activates Sting, leading through
  IKK kinases to Relish-dependent antiviral gene expression.
concepts:
  - {id: GO:0140896, label: cGAS/STING signaling pathway}
parts:
  - id: cgas_like_receptors
    label: cGAS-like receptors
    role: nucleic acid sensors and cyclic dinucleotide synthases
    genes: [cGlr1, cGlr2]
    complex: false
    function: {id: GO:0140699, label: cyclic GMP-AMP synthase activity}
  - id: sting
    label: Sting
    role: cyclic dinucleotide receptor
    genes: [Sting]
    complex: false
    function: {id: GO:0140702, label: cyclic GMP-AMP binding}
  - id: ikk_kinases
    label: IKK kinases
    role: signal-transducing kinases
    genes: [IKKbeta, IKKepsilon]
    complex: false
    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"}
connections:
  - {source: cgas_like_receptors, target: sting, connection_type: PROVIDES_INPUT_FOR,
     description: "Cyclic GMP-AMP made by cGlr1 or cGlr2 binds and activates Sting."}
  - {source: sting, target: ikk_kinases, connection_type: POSITIVELY_REGULATES,
     description: "Activated Sting signals to the IKK kinases."}
  - {source: ikk_kinases, target: relish, connection_type: POSITIVELY_REGULATES,
     description: "IKK-dependent activation of Relish induces Sting-regulated genes."}
knowledge_gaps:
  - gap_statement: >-
      The ligand that activates cGlr2 in vivo, and how Sting is coupled to the
      IKK kinases and Relish in flies (which adaptor, if any, bridges them),
      are not established.
    boundary: Signaling from cGAS-like receptors to Relish.
    gap_kind: [BIOLOGY]
notes: >-
  Boundary. Core components only (FlyBase CGAS-STING-C). IKKbeta and Relish are
  shared with the Imd pathway. The role of IKKepsilon in Sting signaling is
  included because FlyBase lists it as core; no activity is asserted for it
  here. A generic cyclic GMP-AMP synthase activity is used for both cGLRs
  because the two enzymes differ in the cGAMP isomers they make.