Work

Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation

Year: 2020

Type: article

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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.2015632118

Authors: Jargalsaikhan Dagvadorj, Karolina Mikulska-Ruminska, Gantsetseg Tumurkhuu, Rojo A. Ratsimandresy, Jessica Carriere, Allen M. Andres, Stefanie Marek-Iannucci, Yang Song, Shuang Chen, Malcolm Lane, Andrea Dorfleutner, Roberta A. Gottlieb, Christian Stehlik, Suzanne Cassel, Fayyaz S. Sutterwala, Ivet Bahar, Timothy R. Crother, Moshe Arditi

Institutions: Cedars-Sinai Medical Center, University of Pittsburgh, Nicolaus Copernicus University, Cedars-Sinai Smidt Heart Institute, University of California, Los Angeles

Language: English

Topic: Inflammasome and immune disorders

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases

Awards: G1193046719, G1571700926, G1672844487, Mitochondrial DNA Damage and Inflammasome Activation in Vascular Inflammation, G2894863193, G306747657, Targeting the NLRP3 inflammasome to limit pathologic sterile inflammation, G3266566072, Innate Immunity and Host Responses in Pathogenesis of Chlamydia Pneumoniae, Role of IL-1 in Bacterial ligand-induced vasculitis and myocarditis, G4428207565, G4798437132, G534706230, NIDA Center of Excellence OF Computational Drug Abuse Research (CDAR), The role of the inflammasome in plasmacytoid dendritic cells during bacterial infection, G7109394098, G7577646718, CARD-only protein regulation of cytosolic Pattern Recognition Receptor signaling, G8907595608

OpenAlex ID: W3118073673

FWCI: 1.658

Cites: 57

Cited by: 56

Related to: 10