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The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in

Kelvin Ka Lok Wu1, KeKao Long1, Huige Lin1

  • 1Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.

Nature Communications
|November 18, 2021
PubMed

Insights

Early endosome-dependent mitophagy, regulated by APPL1, restricts NLRP3 inflammasome activation. Impaired mitophagy causes inflammation, highlighting endosomes

Area of Science:

  • Cellular Biology
  • Immunology
  • Mitochondrial Biology

Background:

  • Mitophagy, the selective degradation of damaged mitochondria, is recognized for its role in limiting NLRP3 inflammasome activation.
  • However, the precise molecular mechanisms governing this process remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of early endosome-dependent mitophagy in regulating NLRP3 inflammasome activation.
  • To identify key proteins involved in this regulatory pathway.

Main Methods:

  • Investigated the impact of APPL1 deletion on mitophagy and NLRP3 inflammasome activation in macrophages.
  • Utilized biochemical assays to track protein translocation and interactions.
  • Examined disease models in mice with hematopoietic cell-specific APPL1 deficiency.

Main Results:

  • Deletion of APPL1 disrupts early endosome-dependent mitophagy, leading to mitochondrial damage, reactive oxygen species (ROS) production, and oxidized mitochondrial DNA.
  • This disruption triggers NLRP3 inflammasome overactivation in macrophages.
  • APPL1 translocation to mitochondria, mediated by NLRP3 agonists, facilitates mitophagy via Rab5 interaction.
  • APPL1-deficient mice exhibit heightened sensitivity to endotoxin-induced sepsis, obesity-induced inflammation, and glucose dysregulation, associated with elevated interleukin-1β levels.

Conclusions:

  • The early endosomal machinery, through APPL1-mediated mitophagy, is crucial for suppressing NLRP3 inflammasome hyperactivation in macrophages.
  • This pathway plays a significant role in maintaining metabolic and inflammatory homeostasis.

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