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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Lor, 2024. "Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50031-7
    DOI: 10.1038/s41467-024-50031-7
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