Dataset Information

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

ABSTRACT: The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. Here 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. The results suggest we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control regulated by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Benjamin Johnson

LAB HEAD: Rama K Mallampalli

PROVIDER: PXD050224 | Pride | 2024-08-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	021523_70728_CTRL_4uL.raw	Raw
	021523_70728_DARS2-IP-2_4uL.raw	Raw
	021523_70728_DARS2-IP-3_4uL.raw	Raw
	021523_70728_DARS2-IP_1_4uL.raw	Raw
	DARS2.csv	Csv

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Publications

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

Johnson Benjamin S BS Farkas Daniela D El-Mergawy Rabab R Adair Jessica A JA Elhance Ajit A Eltobgy Moemen M Coan Francesca M FM Chafin Lexie L Joseph Jessica A JA Cornwell Alex A Johns Finny J FJ Rosas Lorena L Rojas Mauricio M Farkas Laszlo L Bednash Joseph S JS Londino James D JD Ray Prabir P Ray Anuradha A Kagan Valerian V Lee Janet S JS Chen Bill B BB Mallampalli Rama K RK

Nature communications 20240722 1

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 t ...[more]

PMID: 39039092

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Project description:Background Mortality from bacterial meningitis, predominately caused by Streptococcus pneumoniae, exceeds 50% in low and middle income countries in sub-Saharan Africa with high HIV prevalence. Underlying causes of high mortality are poorly understood. We examined the host and pathogen proteome in adults with proven pneumococcal meningitis (PM), testing if differentially expressed proteins in CSF were implicated in outcome. Materials/methods CSF proteomes were analysed by quantitative Mass-Spectrometry. Spectra were identified using the Swissprot human and TIGR4 pneumococcal protein libraries. Proteins were quantitated and analysed against clinical outcome. Unique proteins in PM were identified against published normal CSF proteome. Random-Forest models were used to test for protein signatures discriminating outcome. Proteins of interest were tested for their effects on growth and opsonophagocytic killing of S. pneumoniae. Results CSF proteomes were available for 57 Adults with PM (median age 32 years, 60% male, 70% HIV-1 co-infected, mortality 63%). 360 individual human and 23 pneumococcal proteins were identified. Of the human protein hits, 30% were not expressed in normal CSF, and these were strongly associated with inflammation and primarily related to neutrophil activity. No human protein signature predicted outcome. However, expression of the essential S. pneumoniae protein Elongation Factor Tu (EF-Tu) was significantly increased in CSF of non-survivors (False Discovery Rate (q) <0.001). Expression of EF-Tu was negatively co-correlated against expression of Neutrophil defensin (r 0.4 p p<0.002), but not against complement proteins C3 or Factor H. In vitro, addition of EF-Tu protein impaired S. pneumoniae neutrophil killing when osponised with CSF. Conclusions Excessive CSF levels of S. pneumoniae EF-Tu protein was associated with reduced survival in human meningitis. Preliminary studies show EF-Tu inhibits neutrophil mediated killing of S. pneumoniae in CSF. Further functional studies are required to better understand the mechanistic role of EF-Tu during PM.