biostudies-literatureJohnson BSNHLBI NIH HHSNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of Health6172https://www.ebi.ac.uk/biostudies/studies/S-EPMC11263397biostudies-literatureUnknown15(1)The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifeNature communicationsTargeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.PMC11263397P30 CA016058R01HL081784R01 HL081784R01HL097376P01 HL114453R01 HL097376R01 HL096376P01HL114453R01HL096376Rojas MFarkas DJoseph JAKagan VEl-Mergawy RChen BBElhance ARay PMallampalli RKAdair JAJohnson BSChafin LLee JSLondino JDJohns FJCoan FMFarkas LRay AEltobgy MBednash JSCornwell ARosas LfalseTargeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 life2024-01-01T00:00:00Z2024 Jul2025-06-01T01:16:40.561Z2025-06-01T01:16:40.561ZS-EPMC112633973903909210.1038/s41467-024-50031-7