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Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
- Source :
- Journal of Clinical Investigation. January 15, 2022, Vol. 132 Issue 2
- Publication Year :
- 2022
-
Abstract
- Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted [H.sub.2][O.sub.2]-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL- 1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL- 1R1dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.<br />Introduction The lung is equipped with a robust proteostasis network for handling protein folding, misfolding, unfolding, and degradation in response to mechanical and environmental stress (1). Consistent with the emerging [...]
- Subjects :
- Homeostasis -- Research
Pharmacology, Experimental
Autophagy (Cytology) -- Physiological aspects -- Health aspects
Mitochondria -- Health aspects -- Physiological aspects
Cellular proteins -- Physiological aspects -- Health aspects
Oxidation-reduction reaction -- Research
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 2
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.691458536
- Full Text :
- https://doi.org/10.1172/JCI144983.