| First Author | van de Veerdonk FL | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 2 | PubMed ID | 34847078 |
| Mgi Jnum | J:320491 | Mgi Id | MGI:6857616 |
| Doi | 10.1172/JCI144983 | Citation | van de Veerdonk FL, et al. (2022) Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy. J Clin Invest 132(2):e144983 |
| abstractText | 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 (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-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-1R1-dependent 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. |
