1. Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation
- Author
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Dagvadorj, Jargalsaikhan, Mikulska-Ruminska, Karolina, Tumurkhuu, Gantsetseg, Ratsimandresy, Rojo A, Carriere, Jessica, Andres, Allen M, Marek-Iannucci, Stefanie, Song, Yang, Chen, Shuang, Lane, Malcolm, Dorfleutner, Andrea, Gottlieb, Roberta A, Stehlik, Christian, Cassel, Suzanne, Sutterwala, Fayyaz S, Bahar, Ivet, Crother, Timothy R, and Arditi, Moshe
- Subjects
2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Autophagy ,Cardiolipins ,Caspase 1 ,Female ,HEK293 Cells ,Humans ,Inflammasomes ,Interleukin-1alpha ,Macrophages ,Male ,Mice ,Mice ,Knockout ,Microtubule-Associated Proteins ,Mitochondria ,Mitophagy ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Protein Binding ,Protein Domains ,Reactive Oxygen Species ,IL-1 alpha ,inflammasome ,mitochondria ,cardiolipin ,autophagy ,IL-1α - 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.
- Published
- 2021