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

Autor:	Dagvadorj J; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Mikulska-Ruminska K; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213.; Institute of Physics, Faculty of Physics Astronomy and Informatics, Nicolaus Copernicus University in Toruń, 87-100 Torun, Poland., Tumurkhuu G; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Ratsimandresy RA; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Carriere J; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Andres AM; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Marek-Iannucci S; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Song Y; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Chen S; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics. David Geffen School of Medicine at University of California, Los Angeles, CA 90095., Lane M; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Dorfleutner A; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Gottlieb RA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Stehlik C; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Cassel S; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Sutterwala FS; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048., Bahar I; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213; bahar@pitt.edu timothy.crother@cshs.org moshe.arditi@cshs.org., Crother TR; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048; bahar@pitt.edu timothy.crother@cshs.org moshe.arditi@cshs.org.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics. David Geffen School of Medicine at University of California, Los Angeles, CA 90095., Arditi M; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048; bahar@pitt.edu timothy.crother@cshs.org moshe.arditi@cshs.org.; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.; Department of Pediatrics. David Geffen School of Medicine at University of California, Los Angeles, CA 90095.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 05; Vol. 118 (1).
DOI:	10.1073/pnas.2015632118
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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