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The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome

Kachiko Hayashi1, Manabu Taura1, Akiko Iwasaki2,3

  • 1Department of Immunobiology, Yale University, New Haven, CT 06520, USA.

Science Signaling
|May 3, 2018
PubMed

Insights

Toll-like receptor 9 (TLR9) signaling requires LC3-associated phagocytosis (LAP) for type I interferon production. LAP recruits IKKα to endosomes, directly linking autophagy to IFN synthesis via TLR9 activation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Toll-like receptor 9 (TLR9) recognizes DNA in endosomes, initiating immune responses.
  • TLR9 signaling activates pathways for proinflammatory cytokines and type I interferons (IFNs).
  • Signaling platform assembly on LC3-decorated endosomes is crucial for IFN production, but not IL-12p40.

Purpose of the Study:

  • To investigate the mechanism linking TLR9 activation to type I IFN production.
  • To elucidate the role of LC3-associated phagocytosis (LAP) in TLR9 signaling.
  • To determine the interaction between autophagy proteins and signaling molecules in TLR9-mediated immunity.

Main Methods:

  • Stimulation of TLR9 with CpG oligonucleotides in immune cells.
  • Recruitment analysis of autophagy protein LC3 and kinase IKKα to TLR9-containing endosomes.
  • Investigation of LAP formation requirements (ATG5, FIP200).
  • Co-immunoprecipitation assays to study protein complex formation (LC3-IKKα, TRAF3, IRF7).
  • Mutagenesis of LC3-interacting regions (LIRs) in IKKα and functional rescue experiments in IKKα-deficient dendritic cells.

Main Results:

  • TLR9 stimulation recruited LC3 and IKKα to endosomes.
  • LAP formation, requiring ATG5, was involved in this recruitment.
  • The LC3-IKKα complex associated with TRAF3 and IRF7.
  • Specific LIRs in IKKα were critical for LC3 binding and type I IFN production.

Conclusions:

  • LC3-associated phagocytosis (LAP) directly links TLR9 activation to IKKα recruitment.
  • This LAP-mediated recruitment is essential for initiating type I IFN production downstream of TLR9.
  • The findings reveal a novel mechanism for regulating innate immune responses via noncanonical autophagy.

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