Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses

Benjamin S. Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A. Adair, Ajit Elhance, Moemen Eltobgy, Francesca M. Coan, Lexie Chafin, Jessica A. Joseph, Alex Cornwell, Finny J. Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S. Bednash, James D. Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S. Lee, Bill B. Chen and Rama K. Mallampalli ()
Additional contact information
Benjamin S. Johnson: The Ohio State University
Daniela Farkas: The Ohio State University
Rabab El-Mergawy: The Ohio State University
Jessica A. Adair: The Ohio State University
Ajit Elhance: The Ohio State University
Moemen Eltobgy: The Ohio State University
Francesca M. Coan: The Ohio State University
Lexie Chafin: The Ohio State University
Jessica A. Joseph: The Ohio State University
Alex Cornwell: The Ohio State University
Finny J. Johns: The Ohio State University
Lorena Rosas: The Ohio State University
Mauricio Rojas: The Ohio State University
Laszlo Farkas: The Ohio State University
Joseph S. Bednash: The Ohio State University
James D. Londino: The Ohio State University
Prabir Ray: and Sleep Medicine
Anuradha Ray: and Sleep Medicine
Valerian Kagan: University of Pittsburgh
Janet S. Lee: Washington University
Bill B. Chen: and Sleep Medicine
Rama K. Mallampalli: The Ohio State University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50031-7

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