Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
Benjamin S JohnsonDaniela FarkasRabab El-MergawyJessica A AdairAjit ElhanceMoemen EltobgyFrancesca M CoanLexie ChafinJessica A JosephAlex CornwellFinny J JohnsLorena RosasMauricio RojasA A Roger ThompsonJoseph S BednashJames D LondinoPrabir RayAnuradha RayValerian E KaganJanet S LeeBill B ChenRama K MallampalliPublished in: Nature communications (2024)
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.
Keyphrases
- small molecule
- protein protein
- innate immune
- immune response
- oxidative stress
- induced apoptosis
- respiratory failure
- high throughput
- diabetic rats
- pulmonary hypertension
- cancer therapy
- community acquired pneumonia
- binding protein
- high glucose
- intensive care unit
- molecular docking
- cell cycle arrest
- candida albicans
- cell death
- amino acid
- single cell