PXD054196

PXD054196 is an original dataset announced via ProteomeXchange.

Title	PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis
Description	Plasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding function. However, in the present study, employing two distinct murine fibrosis models, we show that VTN is not required for PAI-1 to drive lung scarring. This finding suggested that there may be previously unrecognized PAI-1-protein interactions involving the VTN-binding site on PAI-1 and led us to seek novel PAI-1 binding partners that promote fibrosis. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorlA) as the most highly enriched PAI-1 interactor in the injured lung. SorlA is a mosaic receptor implicated in cardiovascular disease and Alzheimer’s dementia, but a role for SorlA in lung fibrosis has not been previously described. In the present study, we found that SorlA deficient mice are protected against the development of lung scarring following injury while SorlA heterozygous mice have an intermediate phenotype. We further determined that the SorlA binding site on PAI-1 overlaps with its VTN-binding site and that mutation of amino acid residues required for VTN-binding also reduce PAI-1 binding to SorlA. We further show that, while VTN deficiency does not influence fibrogenesis in the presence or absence of PAI-1, SorlA is required for PAI-1 to promote scarring. These results, together with data showing increased SorlA levels in human IPF lung tissue, support a novel mechanism through which the potent profibrotic mediator PAI-1 drives lung fibrosis and implicate SorlA as a new therapeutic target in IPF treatment
HostingRepository	PRIDE
AnnounceDate	2025-07-14
AnnouncementXML	Submission_2025-07-13_16:20:27.776.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Sisson
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-24 13:34:28	ID requested
⏵ 1	2025-07-13 16:20:28	announced

10.1172/jci.insight.186131;

Sisson TH, Osterholzer JJ, Leung L, Basrur V, Nesvizhskii A, Subbotina N, Warnock M, Torrente D, Virk AQ, Gutor SS, Horowitz JC, Migliorini M, Strickland DK, Kim KK, Huang SK, Lawrence DA, PAI-1 interaction with sortilin-related receptor 1 is required for lung fibrosis. JCI Insight, 10(11):(2025) [pubmed]

submitter keyword: lung fibrosis,PAI-1

Thomas H. Sisson M.D.
contact affiliation	University of Michigan Medical Center Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine 1150 West Medical Center Drive 6301 MSRB III Ann Arbor, MI 48109-5642
contact email	tsisson@umich.edu
lab head
Thomas Sisson
contact affiliation	University of Michigan Medical School
contact email	tsisson@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054196
     1. Label: PRIDE project
     2. Name: PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis