Autor: |
Sisson TH, Osterholzer JJ, Leung L, Basrur V, Nesvizhskii A, Subbotina N, Warnock M, Torrente D, Virk AQ, Horowitz JC, Migliorini M, Strickland DK, Kim KK, Huang SK, Lawrence DA |
Jazyk: |
angličtina |
Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 08. Date of Electronic Publication: 2024 Aug 08. |
DOI: |
10.1101/2024.08.06.606812 |
Abstrakt: |
Plasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding site. In the present study, employing two distinct murine fibrosis models, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a previously unrecognized profibrotic PAI-1-protein interaction involving the VTN-binding site for PAI-1. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorlA) as the most highly enriched PAI-1 interactor in the fibrosing lung. We next investigated the role of SorlA in pulmonary fibrosis and found that SorlA deficiency protected against lung scarring in a murine model. 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. |
Databáze: |
MEDLINE |
Externí odkaz: |
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