Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation
| Autor: | Moshe Arditi, Roberta A. Gottlieb, Timothy R. Crother, Yang Song, Fayyaz S. Sutterwala, Shuang Chen, Gantsetseg Tumurkhuu, Andrea Dorfleutner, Rojo A. Ratsimandresy, Malcolm Lane, Stefanie Marek-Iannucci, Suzanne L. Cassel, Jessica Carriere, Ivet Bahar, Jargalsaikhan Dagvadorj, Karolina Mikulska-Ruminska, Allen M. Andres, Christian Stehlik |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cardiolipins Inflammasomes Chromosomal translocation Mitochondrion Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Interleukin-1alpha NLR Family Pyrin Domain-Containing 3 Protein Mitophagy Autophagy medicine Cardiolipin Animals Humans Mice Knockout Multidisciplinary Chemistry Macrophages Caspase 1 Inflammasome Biological Sciences Mitochondria Cell biology HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis Female Reactive Oxygen Species Microtubule-Associated Proteins Homeostasis Protein Binding medicine.drug Binding domain |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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