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

ABSTRACT: Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses in bacterial pneumonia

PROVIDER: PRJNA1083050 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28204359_1.fastq.gz	Fastqsanger.gz
	SRR28204359_2.fastq.gz	Fastqsanger.gz
	SRR28204360_1.fastq.gz	Fastqsanger.gz
	SRR28204360_2.fastq.gz	Fastqsanger.gz
	SRR28204361_1.fastq.gz	Fastqsanger.gz

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

Project description: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 DARS2 for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with a robust 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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Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses in bacterial pneumonia

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2024-08-10 | PXD050224 | Pride

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Yeast glutamine tRNA synthetase doxycycline shut-off

Project description:During protein synthesis, charged tRNAs deliver amino acids to translating ribosomes, and are then re-charged by tRNA synthetases (aaRS). In humans, mutant aaRS cause a diversity of neurological disorders, but their molecular aetiologies are incompletely characterised. To understand system responses to aaRS depletion, the yeast glutamine aaRS gene (GLN4) was transcriptionally regulated using doxycycline by tet-off control. Depletion of Gln4p inhibited growth, and induced a transcriptional GCN4 amino acid starvation response, indicative of uncharged tRNA accumulation and Gcn2 kinase activation. The GCN4 response was confirmed using SILAC proteomics, using heavy isotope labelling to identify changes in protein expression during glutamine tRNA synthetase depletion.

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