Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation

Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2015632118. doi: 10.1073/pnas.2015632118.

Abstract

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

Keywords: IL-1α; autophagy; cardiolipin; inflammasome; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy
  • Cardiolipins / metabolism*
  • Cardiolipins / physiology
  • Caspase 1 / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1alpha / metabolism*
  • Interleukin-1alpha / physiology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitophagy / physiology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology
  • Protein Binding / physiology
  • Protein Domains / physiology
  • Reactive Oxygen Species / metabolism

Substances

  • Cardiolipins
  • Inflammasomes
  • Interleukin-1alpha
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Caspase 1