PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis.
Biorxiv : the Preprint Server for Biology
|August 30, 2024
Summary
Plasminogen activator inhibitor-1 (PAI-1) drives lung fibrosis independently of vitronectin. A novel interaction with sortilin related receptor 1 (SorlA) mediates this process, identifying SorlA as a potential therapeutic target for idiopathic pulmonary fibrosis (IPF).
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Biochemistry
Background:
- Plasminogen activator inhibitor-1 (PAI-1) is a known promoter of lung fibrosis.
- Previous understanding suggested PAI-1's profibrotic activity relies on its vitronectin (VTN) binding site.
Purpose of the Study:
- To investigate the mechanism by which PAI-1 promotes lung fibrosis.
- To identify novel protein interactors of PAI-1 involved in pulmonary fibrosis.
- To evaluate the therapeutic potential of targeting these interactions in idiopathic pulmonary fibrosis (IPF).
Main Methods:
- Utilized two distinct murine models of lung fibrosis.
- Employed unbiased proteomics to identify PAI-1 interacting proteins in fibrotic lungs.
- Assessed the role of sortilin related receptor 1 (SorlA) in PAI-1-mediated lung scarring through genetic deficiency models.
- Analyzed SorlA expression in human IPF lung tissues.
Main Results:
- Vitronectin (VTN) is not required for PAI-1 to induce lung scarring.
- Sortilin related receptor 1 (SorlA) was identified as a key PAI-1 interactor in the fibrotic lung.
- SorlA deficiency protected against lung scarring in a murine model.
- SorlA, not VTN, is essential for PAI-1's profibrotic activity.
- Elevated SorlA levels were observed in human IPF lung tissue.
Conclusions:
- PAI-1 promotes lung fibrosis through a novel mechanism involving SorlA, independent of VTN.
- SorlA is a critical mediator of PAI-1-driven pulmonary fibrosis.
- SorlA represents a promising new therapeutic target for IPF treatment.
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