PXD050224-1

PXD050224 is an original dataset announced via ProteomeXchange.

Title	Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses in bacterial pneumonia
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-08-10
AnnouncementXML	Submission_2024-08-10_12:04:27.177.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Benjamin Johnson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine; acetylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-28 13:23:54	ID requested
⏵ 1	2024-08-10 12:04:28	announced

10.1038/s41467-024-50031-7;

Johnson BS, Farkas D, El-Mergawy R, Adair JA, Elhance A, Eltobgy M, Coan FM, Chafin L, Joseph JA, Cornwell A, Johns FJ, Rosas L, Rojas M, Farkas L, Bednash JS, Londino JD, Ray P, Ray A, Kagan V, Lee JS, Chen BB, Mallampalli RK, Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses. Nat Commun, 15(1):6172(2024) [pubmed]

submitter keyword: inflammation, pneumonia,DARS2

Rama K Mallampalli
contact affiliation	S. Robert Davis Chair of Medicine Professor and Chair, Department of Internal Medicine Director, Medical Scientist Training Program
contact email	Rama.Mallampalli2@osumc.edu
lab head
Benjamin Johnson
contact affiliation	The Ohio State University
contact email	benjamin.johnson@osumc.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/08/PXD050224

PRIDE project URI

• PRIDE
  1. PXD050224
     1. Label: PRIDE project
     2. Name: Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses in bacterial pneumonia