Targeted 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 immu...

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Published in:	Nature communications Vol. 15; no. 1; pp. 6172 - 16
Main Authors:	Johnson, Benjamin S., Farkas, Daniela, El-Mergawy, Rabab, Adair, Jessica A., Elhance, Ajit, Eltobgy, Moemen, Coan, Francesca M., Chafin, Lexie, Joseph, Jessica A., Cornwell, Alex, Johns, Finny J., Rosas, Lorena, Rojas, Mauricio, Farkas, Laszlo, Bednash, Joseph S., Londino, James D., Ray, Prabir, Ray, Anuradha, Kagan, Valerian, Lee, Janet S., Chen, Bill B., Mallampalli, Rama K.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 22-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	14/1 631/250 64/110 64/60 692/308 692/420 82/58 Acetylation Animals Aspartate-tRNA ligase Aspartate-tRNA Ligase - genetics Aspartate-tRNA Ligase - metabolism Bacteria Biodegradation Biological properties Cytokines - metabolism Degradation F-Box Proteins - genetics F-Box Proteins - metabolism Female HEK293 Cells Humanities and Social Sciences Humans Immune clearance Immune response Immunity, Innate Immunostimulation Innate immunity Life span Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Mitochondria - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism multidisciplinary Pneumonia Proteins Proteolysis Science Science (multidisciplinary) Transfer RNA tRNA Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination
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Summary:	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 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery. Here, Johnson et al show that bacterial pneumonia induces an interaction between the ubiquitin E3 ligase subunit FBX024 and the mitochondrial protein DARS2 to modulate host immune responses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50031-7