| First Author | Dagvadorj J | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 1 | PubMed ID | 33361152 |
| Mgi Jnum | J:300034 | Mgi Id | MGI:6492395 |
| Doi | 10.1073/pnas.2015632118 | Citation | Dagvadorj J, et al. (2021) Recruitment of pro-IL-1alpha to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation. Proc Natl Acad Sci U S A 118(1):e2015632118 |
| abstractText | 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-1alpha (IL-1alpha)-deficient macrophages have reduced caspase-1 activity and diminished IL-1beta release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1alpha in regulating this balance. LPS priming of macrophages induced pro-IL-1alpha translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1alpha, similar to that found in LC3b. Thus, binding of pro-IL-1alpha to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1beta production. Mutation of pro-IL-1alpha residues predicted to be involved in CL binding resulted in reduced pro-IL-1alpha-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1alpha in regulating mitophagy and the potency of NLRP3 inflammasome activation. |
