Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
Frank L. van de Veerdonk, … , Claudio Costantini, Luigina Romani
Frank L. van de Veerdonk, … , Claudio Costantini, Luigina Romani
Published November 30, 2021
Citation Information: J Clin Invest. 2022;132(2):e144983. https://doi.org/10.1172/JCI144983.
View: Text | PDF
Research Article Infectious disease Inflammation

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

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 (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.

Authors

Frank L. van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M. Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G. Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D’Onofrio, Claudia Stincardini, Luigi Sforna, Monica Borghi, Marilena Castelli, Stefania Pieroni, Vasileios Oikonomou, Valeria R. Villella, Matteo Puccetti, Stefano Giovagnoli, Roberta Galarini, Carolina Barola, Luigi Maiuri, Maria Agnese Della Fazia, Barbara Cellini, Vincenzo Nicola Talesa, Charles A. Dinarello, Claudio Costantini, Luigina Romani

×

Figure 8

Anakinra increases surface expression of p.Phe508del-CFTR via the unconventional secretory pathway.

Options: View larger image (or click on image) Download as PowerPoint
Anakinra increases surface expression of p.Phe508del-CFTR via the unconv...
Cell surface expression of CFTR in HEK293 cells transiently transfected with HA-p.Phe508del-CFTR and HA-WT-CFTR pCDNA3.1 plasmids and treated for 2, 6, or 24 hours with 10 μg/mL of anakinra at 37°C (A). Cells were immunoblotted with the anti-CFTR 596 and anti-calnexin antibodies after cell surface biotinylation and incubation with avidin solution. (B) Immunofluorescence staining of CFTR and GRASP55 in p.Phe508del-CFTR–transfected CFBE41o– cells treated with 10 μg/mL anakinra or vehicle (None) at 37°C. Cells were pretreated with GRASP55 SiRNA or brefeldin A for 24 or 6 hours, respectively, at 37°C. Nuclei were counterstained with DAPI. Data are representative of 3 independent experiments.