PXD038581

PXD038581 is an original dataset announced via ProteomeXchange.

Title	Flucloxacillin-modified proteins identified in primary human hepatocytes
Description	Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 increases susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, the binding of flucloxacillin to human primary hepatocytes was characterized. Flucloxacillin was shown to bind to multiple intracellular proteins including major hepatocellular proteins (haemoglobin and albumin) and mitochondrial proteins (glutamate dehydrogenase and carbamoyl-phosphate synthase). Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. These flucloxacillin-modified intracellular proteins provide a potential source of neo-antigens for HLA-B*57:01 presentation by hepatocytes, that may drive CD8+ T-cell responses. More importantly, covalent binding to mitochondrial proteins, particularly those involved in the metabolism of both endogenous compounds and xenobiotics, could potentially affect their functional activity. This may increase cellular stress signalling and alter the regulatory threshold for activation of the adaptive immune system and thereby play an important role in determining the progression and severity of liver injury. Of particular interest, flucloxacillin binding to Lys50 on 14-3-3 proteins, a key residue within the 14-3-3 protein phospho-binding pocket, could potentially block its binding to signalling proteins as demonstrated by computational modelling, leading to regulating major cellular functions including cell proliferation, growth, apoptosis, autophagy, and cell motility.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:43:24.957.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD038581
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Xiaoli Meng
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	TripleTOF 6600

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-06 07:15:18	ID requested
1	2023-03-11 10:25:07	announced
⏵ 2	2023-11-14 08:43:25	announced	2023-11-14: Updated project metadata.

Ali SE, Waddington JC, Lister A, Sison-Young R, Jones RP, Rehman AH, Goldring CEP, Naisbitt DJ, Meng X, Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. Toxicol Sci, 192(1):106-116(2023) [pubmed]

10.6019/PXD038581;

submitter keyword: primary human hepatocytes,Flucloxaxillin, protein modification

Xiaoli Meng
contact affiliation	University of Liverpool
contact email	xlmeng@liverpool.ac.uk
lab head
Xiaoli Meng
contact affiliation	University of Liverpool
contact email	xlmeng@liverpool.ac.uk
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/2023/03/PXD038581

PRIDE project URI

• PRIDE
  1. PXD038581
     1. Label: PRIDE project
     2. Name: Flucloxacillin-modified proteins identified in primary human hepatocytes