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bioRxiv · 10.1101/2024.08.06.606812

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

Sisson, T. H.·Osterholzer, J. J.·Leung, L.·Basrur, V.·Nesvizhskii, A.·Subbotina, N.·Warnock, M.·Torrente, D.·Virk, A. Q.·Horowitz, J. C.·Migliorini, M.·Strickland, D. K.·Kim, K. K.·Huang, S. K.·Lawrence, D. A.
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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 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.

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Sisson, T. H., Osterholzer, J. J., Leung, L., Basrur, V., Nesvizhskii, A., Subbotina, N., Warnock, M., Torrente, D., Virk, A. Q., Horowitz, J. C., Migliorini, M., Strickland, D. K., Kim, K. K., Huang, S. K., Lawrence, D. A.. 2024-08-08. PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis. https://doi.org/10.1101/2024.08.06.606812

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