TY - JOUR
T1 - Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses
AU - Johnson, Benjamin S.
AU - Farkas, Daniela
AU - El-Mergawy, Rabab
AU - Adair, Jessica A.
AU - Elhance, Ajit
AU - Eltobgy, Moemen
AU - Coan, Francesca M.
AU - Chafin, Lexie
AU - Joseph, Jessica A.
AU - Cornwell, Alex
AU - Johns, Finny J.
AU - Rosas, Lorena
AU - Rojas, Mauricio
AU - Farkas, Laszlo
AU - Bednash, Joseph S.
AU - Londino, James D.
AU - Ray, Prabir
AU - Ray, Anuradha
AU - Kagan, Valerian
AU - Lee, Janet S.
AU - Chen, Bill B.
AU - Mallampalli, Rama K.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85199263869&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-50031-7
DO - 10.1038/s41467-024-50031-7
M3 - Article
C2 - 39039092
AN - SCOPUS:85199263869
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6172
ER -