Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

• Published in: Cell reports (Cambridge) Vol. 42; no. 5; p. 112473
• Main Authors: Melamed, Shay, Zaffryar-Eilot, Shelly, Nadjar-Boger, Elisabeth, Aviram, Rohtem, Zhao, Huaning, Yaseen-Badarne, Wesal, Kalev-Altman, Rotem, Sela-Donenfeld, Dalit, Lewinson, Oded, Astrof, Sophie, Hasson, Peleg, Wolfenson, Haguy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.05.2023; Elsevier
• Subjects: Cell Adhesion; Cell Movement; Extracellular Matrix - metabolism; fibronectin fibrillogenesis; Fibronectins - metabolism; Integrins - metabolism; lysyl oxidaze family; mechanosensing; mechanosensing; fibronectin fibrillogenesis; CP: Cell biology; lysyl oxidaze family; cell adhesion
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112473

Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here, we identify a nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl oxidase enzyme family members. This oxidation induces fibronectin clustering, which promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cell colony formation in soft agar as well as collective and single-cell migration. These results reveal a force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing. [Display omitted] •Lysyl oxidase (LOX) enzyme family oxidize lysine residues within fibronectin•The LOX family enzymatic activity initiates fibronectin (FN) fibrillogenesis•LOX oxidation of FN is essential for FN fibrillogenesis•Abrogation of oxidation sites impairs cell adhesion, migration, and proliferation Melamed et al. show that initiation of fibronectin fibrillogenesis is mediated by the LOX enzyme family, which oxidizes lysine residues within fibronectin. This, in turn, leads to fibronectin clustering, which is a prerequisite for adhesion and force-dependent fibrillogenesis. Mutations in fibronectin-oxidation sites lead to impaired cell adhesion, migration, and proliferation.