期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：49
页码：17528-17533
DOI：10.1073/pnas.1417686111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCellular activities are regulated by signaling pathways in which information is transduced biochemically. Increasingly it is appreciated that regulation also involves mechanical signaling, where mechanical information is mechanotransduced into biochemical information. However, little is understood about the cooperation of mechanical and biochemical signaling in mixed pathways. We identified a pathway where the two types of signaling work in harmony to remodel actomyosin stress fibers in the cell's cytoskeleton. We present evidence that expansion or contraction of fibers alters the actin filament overlap, a mechanical signal that is mechanotransduced into actin assembly or disassembly, which in turn alters the overlap. A mathematical model accurately describes our measurements and shows that this mechanical-biochemical feedback loop synchronizes actin remodeling with fiber length changes. Cytoskeletal actin assemblies transmit mechanical stresses that molecular sensors transduce into biochemical signals to trigger cytoskeletal remodeling and other downstream events. How mechanical and biochemical signaling cooperate to orchestrate complex remodeling tasks has not been elucidated. Here, we studied remodeling of contractile actomyosin stress fibers. When fibers spontaneously fractured, they recoiled and disassembled actin synchronously. The disassembly rate was accelerated more than twofold above the resting value, but only when contraction increased the actin density to a threshold value following a time delay. A mathematical model explained this as originating in the increased overlap of actin filaments produced by myosin II-driven contraction. Above a threshold overlap, this mechanical signal is transduced into accelerated disassembly by a mechanism that may sense overlap directly or through associated elastic stresses. This biochemical response lowers the actin density, overlap, and stresses. The model showed that this feedback mechanism, together with rapid stress transmission along the actin bundle, spatiotemporally synchronizes actin disassembly and fiber contraction. Similar actin remodeling kinetics occurred in expanding or contracting intact stress fibers but over much longer timescales. The model accurately described these kinetics, with an almost identical value of the threshold overlap that accelerates disassembly. Finally, we measured resting stress fibers, for which the model predicts constant actin overlap that balances disassembly and assembly. The overlap was indeed regulated, with a value close to that predicted. Our results suggest that coordinated mechanical and biochemical signaling enables extended actomyosin assemblies to adapt dynamically to the mechanical stresses they convey and direct their own remodeling.
