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Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
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.
Afiliación
  • Johnson BS; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Farkas D; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • El-Mergawy R; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Adair JA; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Elhance A; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Eltobgy M; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Coan FM; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Chafin L; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Joseph JA; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Cornwell A; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Johns FJ; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Rosas L; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Rojas M; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Farkas L; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Bednash JS; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Londino JD; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
  • Ray P; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, the University of Pittsburgh, Pittsburgh, PA, and Sleep Medicine, Pittsburgh, PA, USA.
  • Ray A; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, the University of Pittsburgh, Pittsburgh, PA, and Sleep Medicine, Pittsburgh, PA, USA.
  • Kagan V; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Lee JS; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, USA.
  • Chen BB; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, the University of Pittsburgh, Pittsburgh, PA, and Sleep Medicine, Pittsburgh, PA, USA.
  • Mallampalli RK; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA. rama.mallampalli2@osumc.edu.
Nat Commun ; 15(1): 6172, 2024 Jul 22.
Article en En | MEDLINE | ID: mdl-39039092
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Aspartato-ARNt Ligasa / Ratones Noqueados / Ubiquitinación / Inmunidad Innata / Mitocondrias Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Aspartato-ARNt Ligasa / Ratones Noqueados / Ubiquitinación / Inmunidad Innata / Mitocondrias Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos