PXD020546

PXD020546 is an original dataset announced via ProteomeXchange.

Title	Recombinant TSP1 cleaved by HTRA1 (LCMS)
Description	HTRA1 proteolysis of TSP1 inhibits immune suppression in age-related macular degeneration. A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age related macular degeneration (AMD), a major cause of blindness affecting millions of individuals worldwide. Here we show that monocytes (Mo) from homozygous carriers of the 10q26 AMD-risk haplotype overexpress the High-Temperature Requirement A Serine Peptidase 1 (HTRA1), which locates to mononuclear phagocytes (MP) in eyes of patients with AMD. Elevated HTRA1 led to significant subretinal Mo persistence and promoted pathogenic MP accumulation due to the hydrolysis of Thrombospondin 1 (TSP1). Mechanistically, we demonstrate that HTRA1 separates TSP1’s two CD47- binding Valine-Valine-Methionine-sites that are necessary for efficient CD47 activation and repression of osteopontin (OPN) secretion, a mediator of inflammation and wound healing. Accordingly, OPN was overexpressed in early Mo-derived macrophages in 10q26 risk carriers and OPN deletion or inhibition fully reversed HTRA1- induced pathogenic MP persistence. Our observations provide new insights into the molecular mechanisms of MP accumulation in inflammation and show that HTRA1 resistant CD47 agonists and OPN inhibitors can provide a powerful tool to reverse HTRA1’s pro-inflammatory effect and restore retinal immune suppression in AMD, critical for retinal homeostasis.
HostingRepository	PRIDE
AnnounceDate	2020-07-25
AnnouncementXML	Submission_2020-08-22_16:44:53.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Solenne Chardonnet
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	HCTultra

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-23 17:59:38	ID requested
1	2020-07-24 17:46:50	announced
⏵ 2	2020-08-22 16:44:54	announced	2020-08-23: Updated publication reference for PubMed record(s): 32814029.

Beguier F, Housset M, Roubeix C, Augustin S, Zagar Y, Nous C, Mathis T, Eandi C, Benchaboune M, Drame-Maign, é A, Carpentier W, Chardonnet S, Touhami S, Blot G, Conart JB, Charles-Messance H, Potey A, Girmens JF, Paques M, Blond F, Leveillard T, Koertvely E, Roger JE, Sahel JA, Sapieha P, Delarasse C, Guillonneau X, Sennlaub F, The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination. Immunity, 53(2):429-441.e8(2020) [pubmed]

submitter keyword: TSP1, HTRA1

Solenne Chardonnet
contact affiliation	Sorbonne Université UMS PASS P3S core facility
contact email	solenne.chardonnet@sorbonne-universite.fr
lab head
Solenne Chardonnet
contact affiliation	Sorbonne Universite UMS PASS - P3S
contact email	solenne.chardonnet@sorbonne-universite.fr
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/2020/07/PXD020546

PRIDE project URI

• PRIDE
  1. PXD020546
     1. Label: PRIDE project
     2. Name: Recombinant TSP1 cleaved by HTRA1 (LCMS)