2. Academic Validation
  3. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses

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

  • Nat Commun. 2024 Jul 22;15(1):6172. doi: 10.1038/s41467-024-50031-7.
Benjamin S Johnson 1,  Daniela Farkas 1,  Rabab El-Mergawy 1,  Jessica A Adair 1,  Ajit Elhance 1,  Moemen Eltobgy 1,  Francesca M Coan 1,  Lexie Chafin 1,  Jessica A Joseph 1,  Alex Cornwell 1,  Finny J Johns 1,  Lorena Rosas 1,  Mauricio Rojas 1,  Laszlo Farkas 1,  Joseph S Bednash 1,  James D Londino 1,  Prabir Ray 2,  Anuradha Ray 2,  Valerian Kagan 3,  Janet S Lee 4,  Bill B Chen 2,  Rama K Mallampalli 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • 2 Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, the University of Pittsburgh, Pittsburgh, PA, and Sleep Medicine, Pittsburgh, PA, USA.
  • 3 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, USA.
  • 5 Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA. rama.mallampalli2@osumc.edu.
PMID: 39039092 DOI: 10.1038/s41467-024-50031-7
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.

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