Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
Cell Rep. 2023 May 30;42(5):112473. doi: 10.1016/j.celrep.2023.112473. Epub 2023 May 5.
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.
纤连蛋白原纤维的形成和机械感知都依赖于整合素介导的力传递到细胞外基质。然而，力传递本身依赖于原纤维的形成，并且纤连蛋白原纤维存在于不能施加高力的柔软胚胎中，这表明力不可能是原纤维形成的唯一启动因素。在这里，我们确定了一个在力传递之前的成核步骤，该步骤由赖氨酰氧化酶家族成员介导的纤连蛋白氧化驱动。这种氧化诱导纤连蛋白聚集，促进早期黏附，改变细胞对软基质的反应，并增强力向基质的传递。相比之下，缺乏纤连蛋白氧化会破坏原纤维的形成，扰乱细胞-基质黏附，并损害机械感知。此外，纤连蛋白氧化促进了软琼脂中的癌细胞集落形成以及细胞的集体和单细胞迁移。这些结果揭示了一种力非依赖的、酶依赖的机制，该机制启动了纤连蛋白原纤维的形成，确立了细胞黏附和机械感知中的一个关键步骤。
