Initiation of fibronectin fibrillogenesis is an enzyme-dependent process
Shay Melamed,
Shelly Zaffryar-Eilot,
Elisabeth Nadjar-Boger,
Rohtem Aviram,
Huaning Zhao,
Wesal Yaseen-Badarne,
Rotem Kalev-Altman,
Dalit Sela-Donenfeld,
Oded Lewinson,
Sophie Astrof,
Peleg Hasson,
Haguy Wolfenson
Affiliations
Shay Melamed
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Shelly Zaffryar-Eilot
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Elisabeth Nadjar-Boger
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Rohtem Aviram
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Huaning Zhao
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
Wesal Yaseen-Badarne
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Rotem Kalev-Altman
Koret School of Veterinary Medicine, Faculty of Agriculture, Food and Environmental Sciences, The Hebrew University, Rehovot, Israel
Dalit Sela-Donenfeld
Koret School of Veterinary Medicine, Faculty of Agriculture, Food and Environmental Sciences, The Hebrew University, Rehovot, Israel
Oded Lewinson
Department of Molecular Microbiology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel
Sophie Astrof
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
Peleg Hasson
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel; Corresponding author
Haguy Wolfenson
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa 31096, Israel; Corresponding author
Summary: 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.
