FSTL1 promotes alveolar epithelial cell aging and worsens pulmonary fibrosis by affecting SENP1-mediated DeSUMOylation

Cell Biol Int. 2023 Oct;47(10):1716-1727. doi: 10.1002/cbin.12062. Epub 2023 Jun 27.

Abstract

Alveolar epithelial cell (AEC) senescence-induced changes of lung mesenchymal cells are key to starting the progress of pulmonary fibrosis. Follistatin-like 1 (FSTL1) plays a central regulatory role in the complex process of senescence and pulmonary fibrosis by enhancing transforming growth factor-β1 (TGF-β1) signal pathway activity. Activation of Smad4 and Ras relies on SUMO-specific peptidase 1 (SENP1)-mediated deSUMOylation during TGF-β signaling pathway activation. We hypothesized that SENP1-mediated deSUMOylation may be a potential therapeutic target by modulating FSTL1-regulated cellular senescence in pulmonary fibrosis. In verifying this hypothesis, we found that FSTL1 expression was upregulated in the lung tissues of patients with idiopathic pulmonary fibrosis and that SENP1 was overexpressed in senescent AECs. TGF-β1-induced FSTL1 not only promoted AEC senescence but also upregulated SENP1 expression. Interfering with SENP1 expression inhibited FSTL1-dependent promotion of AEC senescence and improved pulmonary fibrosis in mouse lungs. FSTL1 enhancement of TGF-β1 signaling pathway activation was dependent on SENP1 in senescent AEC. Our work identifies a novel mechanism by which FSTL1 is involved in AEC senescence. Inhibition of SENP1 in epithelial cells alleviated pulmonary fibrosis by blocking FSTL1-enhanced TGF signaling.

Keywords: FSTL1; SENP1; alveolar epithelial cell; pulmonary fibrosis; senescence.

MeSH terms

  • Aging
  • Alveolar Epithelial Cells
  • Animals
  • Follistatin-Related Proteins* / metabolism
  • Idiopathic Pulmonary Fibrosis* / metabolism
  • Mice
  • Peptide Hydrolases / metabolism
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Follistatin-Related Proteins
  • Peptide Hydrolases
  • Transforming Growth Factor beta1
  • Fstl1 protein, mouse
  • Senp1 protein, mouse