| First Author | Southern BD | Year | 2024 |
| Journal | J Biol Chem | Volume | 300 |
| Issue | 1 | Pages | 105530 |
| PubMed ID | 38072048 | Mgi Jnum | J:344374 |
| Mgi Id | MGI:7575101 | Doi | 10.1016/j.jbc.2023.105530 |
| Citation | Southern BD, et al. (2023) A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis. J Biol Chem 300(1):105530 |
| abstractText | Fibroblast to myofibroblast transdifferentiation mediates numerous fibrotic disorders, such as idiopathic pulmonary fibrosis (IPF). We have previously demonstrated that non-muscle myosin II (NMII) is activated in response to fibrotic lung extracellular matrix, thereby mediating myofibroblast transdifferentiation. NMII-A is known to interact with the calcium-binding protein S100A4, but the mechanism by which S100A4 regulates fibrotic disorders is unclear. In this study, we show that fibroblast S100A4 is a calcium-dependent, mechanoeffector protein that is uniquely sensitive to pathophysiologic-range lung stiffness (8-25 kPa) and thereby mediates myofibroblast transdifferentiation. Re-expression of endogenous fibroblast S100A4 rescues the myofibroblastic phenotype in S100A4 KO fibroblasts. Analysis of NMII-A/actin dynamics reveals that S100A4 mediates the unraveling and redistribution of peripheral actomyosin to a central location, resulting in a contractile myofibroblast. Furthermore, S100A4 loss protects against murine in vivo pulmonary fibrosis, and S100A4 expression is dysregulated in IPF. Our data reveal a novel mechanosensor/effector role for endogenous fibroblast S100A4 in inducing cytoskeletal redistribution in fibrotic disorders such as IPF. |
