학술논문
Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation
Document Type
article
Author
Dagvadorj, Jargalsaikhan; Mikulska-Ruminska, Karolina; Tumurkhuu, Gantsetseg; Ratsimandresy, Rojo A; Carriere, Jessica; Andres, Allen M; Marek-Iannucci, Stefanie; Song, Yang; Chen, Shuang; Lane, Malcolm; Dorfleutner, Andrea; Gottlieb, Roberta A; Stehlik, Christian; Cassel, Suzanne; Sutterwala, Fayyaz S; Bahar, Ivet; Crother, Timothy R; Arditi, Moshe
Source
Proceedings of the National Academy of Sciences of the United States of America. 118(1)
Subject
Language
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.