PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis

ABSTRACT: 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

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Diffuse Pulmonary Fibrosis

SUBMITTER: Thomas Sisson  

LAB HEAD: Thomas H. Sisson M.D.

PROVIDER: PXD054196 | Pride | 2025-07-14

REPOSITORIES: Pride