PXD014033-1

PXD014033 is an original dataset announced via ProteomeXchange.

Title	Protein-tyrosine kinase 2-beta activates Interferon Regulatory Factor 5 to control inflammation
Description	Interferon regulatory factor 5 (IRF5) plays a distinct role in the regulation of immune responses in health and disease and is a genetic risk factor several autoimmune conditions, including systemic lupus erythematosus, diabetes, arthritis and inflammatory bowel disease. IRF5 function as a transcription factor requires post-translational modifications of the protein such as phosphorylation. Though several upstream signalling regulators of IRF5 have been identified, there is as yet little understanding of how they control IRF5 activity or whether other unknown kinases are involved. In this study, we systematically searched for IRF5 kinases using a reporter-based method for screening a library of 365 inhibitors of protein kinases. Based on the pool of the identified IRF5-inhibiting compounds we have compiled a list of putative IRF5 kinases, which we tested in subsequent in vitro assays. Protein-tyrosine kinase 2-beta (Ptk2b or PYK2) was one of the top hits, capable of binding to and phosphorylating mouse IRF5 at tyrosine (Y) 171. We have shown that IRF5 recruitment to target genes and IRF5-dependent transcription was impaired in cells treated with highly selective PYK2 inhibitors or in PYK2-deficient cells. Moreover, expression of pro-inflammatory cytokines was blocked in the supernatants of human biopsies from inflamed colon of patients with ulcerative colitis and treated ex vivo with a PYK2 inhibitor. Thus, we have identified a major role for PYK2 in regulating the inflammatory response and mapped its activity to the IRF5 innate sensing pathways.
HostingRepository	PRIDE
AnnounceDate	2021-10-14
AnnouncementXML	Submission_2021-10-13_23:09:35.763.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD014033
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Roman Fischer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	Ammonia-loss; GG; Amidated; Isopropylphospho; Methyl; Oxidation; AEC-MAEC; Pro->pyro-Glu; Carboxy; Ethanedithiol; Propionamide; Phospho; Didehydro; Cation:Na; Deamidated; Trp->Kynurenin; Acetyl; Deoxy; Formyl; Carbamyl; HexNAc; Lys->Allysine; Carbamidomethyl; Cation:Ca[II]; Gln->pyro-Glu; Guanidinyl; Menadione-HQ; Glu->pyro-Glu; O-Methylphosphate; Ammonium; Dehydrated; Dimethyl; Biotin; Dioxidation; Hydroxymethyl; MercaptoEthanol; Carbofuran
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-28 01:52:09	ID requested
⏵ 1	2021-10-13 23:09:36	announced

Dataset with its publication pending

submitter keyword: IRF5, PYK2

Roman Fischer
contact affiliation	Discovery Proteomics Facility Oxford
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Roman Fischer
contact affiliation	University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014033
     1. Label: PRIDE project
     2. Name: Protein-tyrosine kinase 2-beta activates Interferon Regulatory Factor 5 to control inflammation