PXD005613-1

PXD005613 is an original dataset announced via ProteomeXchange.

Title	Nitration of Tyrosines In Complement Factor H Domains Alters Its Immunological Activity and Mediates A Pathogenic Role In Age Related Macular Degeneration
Description	Nitrosative stress has been implicated in the pathogenesis of age related macular degeneration (AMD). Tyrosine nitration is a unique type of post translational modification that occurs in the setting of inflammation and nitrosative stress. To date, the significance and functional implications of tyrosine nitration of complement factor H (CFH), a key complement regulator in the eye has not been explored, and is examined in this study in the context of AMD pathogenesis. Sections of eyes from deceased individuals with AMD (n = 5) demonstrated the presence of immunoreactive nitrotyrosine CFH. We purified nitrated CFH from retinae from 2 AMD patients. Mass spectrometry of CFH isolated from AMD eyes revealed residues in domains critical for binding to heparan sulphate glycosaminoglycans (GAGs), lipid peroxidation by-products and complement (C) 3b were nitrated. Functional studies revealed that nitrated CFH did not bind to lipid peroxidation products, nor to the GAG of perlecan nor to C3b. There was loss of cofactor activity for Factor I mediated cleavage of C3b with nitrated CFH compared to non-nitrated CFH. CFH inhibits, but nitrated CFH significantly potentiates, the secretion of the pro-inflammatory and angiogenic cytokine IL-8 from monocytes that have been stimulated with lipid peroxidation by-products. AMD patients (n = 30) and controls (n = 30) were used to measure plasma nitrated CFH using a novel ELISA. AMD patients had significantly elevated nitrated CFH levels compared to controls (p = 0.0117). These findings strongly suggest that nitrated CFH contributes to AMD progression, and is a target for therapeutic intervention.
HostingRepository	PRIDE
AnnounceDate	2017-08-29
AnnouncementXML	Submission_2017-08-29_03:36:30.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD005613
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	J Wong
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Nitro; Oxidation; Acetyl; Carbamidomethyl
Instrument	LTQ FT

Revision	Datetime	Status	ChangeLog Entry
0	2016-12-21 02:06:59	ID requested
⏵ 1	2017-08-29 03:36:32	announced

Krilis M, Qi M, Madigan MC, Wong JWH, Abdelatti M, Guymer RH, Whitelock J, McCluskey P, Zhang P, Qi J, Hunyor AP, Krilis SA, Giannakopoulos B, Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration. Oncotarget, 8(30):49016-49032(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: Nitrotyrosine, Macular Degeneration, Complement Factor H, CFH

Steven Krilis
contact affiliation	Department of Infectious Diseases, Immunology and Sexual Health and Department of Medicine, St George Hospital, University of New South Wales, 2 South Street, Kogarah, Sydney, NSW 2217, Australia
contact email	s.krilis@unsw.edu.au
lab head
J Wong
contact affiliation	Medicine
contact email	jason.wong@unsw.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD005613
     1. Label: PRIDE project
     2. Name: Nitration of Tyrosines In Complement Factor H Domains Alters Its Immunological Activity and Mediates A Pathogenic Role In Age Related Macular Degeneration